Azole derivatives and fused bicyclic azole derivatives as therapeutic agents

ABSTRACT

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer&#39;s disease, erectile dysfunction, and tumor invasion and metastasis.

STATEMENT OF RELATED APPLICATION

This application is a continuation application of pending U.S. patentapplication Ser. No. 12/799,971, filed May 5, 2010, entitled “AzoleDerivatives and Fused Bicyclic Azole Derivatives as Therapeutic Agents”which is a divisional application of U.S. patent application Ser. No.11/511,163, filed Aug. 28, 2006, entitled “Azole Derivatives and FusedBicyclic Azole Derivatives as Therapeutic Agents,” now issued as U.S.Pat. No. 7,714,013, which is a divisional application of U.S. patentapplication Ser. No. 10/382,203, filed Mar. 5, 2003, entitled “AzoleDerivatives and Fused Bicyclic Azole,” now issued as U.S. Pat. No.7,361,678, which claims priority under 35 U.S.C. §119(e) from U.S.Provisional Application No. 60/361,983, filed Mar. 5, 2002, entitled“Azole Derivatives as Therapeutic Agents.” and which are eachincorporated by reference in their entitieties herewith.

FIELD OF THE INVENTION

This invention relates to compounds which are modulators of the receptorfor advanced glycated end products (RAGE) and interaction with itsligands such as advanced glycated end products (AGEs),S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, for the management,treatment, control, or as an adjunct treatment of diseases caused byRAGE.

BACKGROUND OF THE INVENTION

Incubation of proteins or lipids with aldose sugars results innonenzymatic glycation and oxidation of amino groups on proteins to formAmadori adducts. Over time, the adducts undergo additionalrearrangements, dehydrations, and cross-linking with other proteins toform complexes known as Advanced Glycosylation End Products (AGEs).Factors which promote formation of AGEs included delayed proteinturnover (e.g. as in amyloidoses), accumulation of macromolecules havinghigh lysine content, and high blood glucose levels (e.g. as in diabetes)(Hori et al., J. Biol. Chem. 270: 25752-761, (1995)). AGEs haveimplicated in a variety of disorders including complications associatedwith diabetes and normal aging.

AGEs display specific and saturable binding to cell surface receptors onendothelial cells of the microvasculature, monocytes and macrophages,smooth muscle cells, mesengial cells, and neurons. The Receptor forAdvanced Glycated Endproducts (RAGE) is a member of the immunoglobulinsuper family of cell surface molecules. The extracellular (N-terminal)domain of RAGE includes three immunoglobulin-type regions, one V(variable) type domain followed by two C-type (constant) domains (Neeperet al., J. Biol. Chem. 267:14998-15004 (1992)). A single transmembranespanning domain and a short, highly charged cytosolic tail follow theextracellular domain. The N-terminal, extracellular domain can beisolated by proteolysis of RAGE to generate soluble RAGE (sRAGE)comprised of the V and C domains.

RAGE is expressed in most tissues, and in particular, is found incortical neurons during embryogenesis (Hoh et al., J. Biol. Chem.270:25752-761 (1995)). Increased levels of RAGE are also found in agingtissues (Schleicher at al., J. Clin. Invest. 99 (3): 457-468 (1997)),and the diabetic retina, vasculature and kidney (Schmidt et al., NatureMed. 1:1002-1004 (1995)). Activation of RAGE in different tissues andorgans leads to a number of pathophysiological consequences. RAGE hasbeen implicated in a variety of conditions including: acute and chronicinflammation (Hofmann at al., Cell 97:889-901 (1999)), the developmentof diabetic late complications such as increased vascular permeability(Wautier et al., J. Clin. Invest 97:238-243 (1995)), nephropathy(Teillet et al., J. Am. Soc. Nephrol. 11:1488-1497 (2000)),atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM,Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al.,Diabetologia 42:603-607 (1999)). RAGE has also been implicated inAlzheimer's disease (Yan at al., Nature 382: 685-691, (1996)), erectiledysfunction, and in tumor invasion and metastasis (Taguchi at al.,Nature 405: 354-357, (2000)).

In addition to AGEs, other compounds can bind to, and modulate RAGE. Innormal development, RAGE interacts with amphoterin, a polypeptide whichmediates neurite outgrowth in cultured embryonic neurons (Hori et at,1995). RAGE has also been shown to interact with EN-RAGE, a proteinhaving substantial similarity to calgranulin (Hofmann et al., Cell97:889-901 (1999)). RAGE has also been shown to interact with β-amyloid(Yan et al., Nature 389:589-595, (1997); Yan et al., Nature 382:685-691(1996); Yan et al., Proc. Natl Acad. Sci., 94:5296-5301 (1997)).

Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE, β-amyloid,CML (N^(ε)—Carboxymethyl lysine), and amphoterin to RAGE has been shownto modify expression of a variety of genes. For example, in many celltypes interaction between RAGE and its ligands generates oxidativestress, which thereby results in activation of the free radicalsensitive transcription factor NF-κB, and the activation of NF-κBregulated genes, such as the cytokines IL-1β, TNF-α, and the like. Inaddition, several other regulatory pathways, such as those involving p21ras, MAP kinases, ERK1 and ERK2, have been shown to be activated bybinding of AGEs and other ligands to RAGE. In fact, transcription ofRAGE itself is regulated at least in part by NF-κB. Thus, an ascending,and often detrimental, spiral is fueled by a positive feedback loopinitiated by ligand binding. Antagonizing binding of physiologicalligands to RAGE, therefore, is our target for down-regulation of thepathophysiological changes brought about by excessive concentrations ofAGEs and other ligands for RAGE.

Thus, there is a need for the development of compounds that antagonizebinding of physiological ligands to the RAGE receptor.

SUMMARY OF THE INVENTION

This invention provides substituted benzimidazole compounds. Embodimentsof the present invention provide compounds of Formula (I) as depictedbelow, methods of their preparation, pharmaceutical compositionscomprising the compounds, and methods for their use in treating human oranimal disorders. Compounds of the invention are useful as modulators ofthe interaction of the receptor for advanced glycated end products(RAGE) with its ligands such as advanced glycated end products (AGEs),S100/calgranulin/EN-RAGE, β-amyloid and amphoterin. The compounds areuseful in a variety of applications including the management, treatment,control, and/or as an adjunct of diseases in humans caused by RAGE. Suchdiseases or disease states include acute and chronic inflammation, thedevelopment of diabetic late complications such as increased vascularpermeability, nephropathy, atherosclerosis, and retinopathy, thedevelopment of Alzheimer's disease, erectile dysfunction, and tumorinvasion and metastasis.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides certain substitutedazole compounds. Such compounds are useful in the modulation, preferablyin the inhibition, of the interaction of RAGE with its physiologicalligands, as will be discussed in more detail below.

In a second aspect, the present invention provides compounds of Formula(I):

wherein

-   R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl,    -heterocyclyl, -alkyl, -alkenyl, -alkynyl, -alkylene-aryl,    -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl,    -fused cycloalkylaryl, -fused cycloalkylheteroaryl, -fused    heterocyclylaryl, -fused heterocyclylheteroaryl, -alkylene-fused    cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl,    -alkylene-fused heterocyclylaryl, -alkylene-fused    heterocyclylheteroaryl, or -G₁-G₂-G₃-R₅    -   wherein        -   G₁ and G₃ independently comprise alkylene, alkenylene,            alkynylene, cycloalkylene, heterocyclylene, arylene,            heteroarylene, (aryl)alkylene, (heteroaryl)alkylene,            (aryl)alkenylene, (heteroaryl)alkenylene, or a direct bond;        -   G₂ comprises —O—, —S—, —S(O)—, —N(R₆)—, —S(O)₂—, —C(O)—,            —O—C(O)—, —C(O)—O—, —C(O)N(R₆)—, —N(R₆)C(O)—, —S(O₂)N(R₆)—,            N(R₆)S(O₂)—, —O-alkylene-C(O)—, —(O)C-alkylene-O—,            —O-alkylene-, -alkylene-O—, alkylene, alkenylene,            alkynylene, cycloalkylene, heterocyclylene, arylene,            heteroarylene, fused cycloalkylarylene, fused            cycloalkylheteroarylene, fused heterocyclylarylene, fused            heterocyclylheteroarylene, or a direct bond, wherein R₆            comprises hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy, or            -alkylene-O-aryl; and        -   R₅ comprises hydrogen, aryl, heteroaryl, cycloalkyl,            heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,            -alkylene-heteroaryl, -alkylene-heterocyclyl,            -alkylene-cycloalkyl, fused cycloalkylaryl, fused            cycloalkylheteroaryl, fused heterocyclylaryl, fused            heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl,            -alkylene-fused cycloalkylheteroaryl, -alkylene-fused            heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl;-   A₁ comprises O, S, or —N(R₂)—;    -   wherein        -   R₂ comprises            -   a) —H;            -   b) -aryl;            -   c) -heteroaryl;            -   d) -cycloalkyl            -   e) heterocyclyl;            -   f) -alkyl;            -   g) -alkenyl;            -   h) -alkynyl;            -   i) -alkylene-aryl,            -   j) -alkylene-heteroaryl,            -   k) -alkylene-heterocyclyl,            -   l) -alkylene-cycloalkyl;            -   m)-fused cycloalkylaryl,            -   n)-fused cycloalkylheteroaryl,            -   o) -fused heterocyclylaryl,            -   p) -fused heterocyclylheteroaryl;            -   q) -alkylene-fused cycloalkylaryl,            -   r) -alkylene-fused cycloalkylheteroaryl,            -   s) -alkylene-fused heterocyclylaryl,            -   t) -alkylene-fused heterocyclylheteroaryl; or            -   u) a group of the formula

-   -   -   -   -   wherein                -    A₃ comprises an aryl or heteroaryl group;                -    L₁ and L₂ independently comprise alkylene or                    alkenylene; and                -    L₃ comprises a direct bond, alkylene, —O—, —S—,                    —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₃₀, R₃₁, and R₃₂ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, alkylene-aryl, or                    -alkylene-heteroaryl;

-   R₃ and R₄ independently comprise    -   a) -hydrogen,    -   b) -halogen,    -   c)-hydroxyl,    -   d) -cyano,    -   e) -carbamoyl,    -   f) -carboxyl,    -   g) -aryl,    -   h) -heteroaryl,    -   i) -cycloalkyl,    -   j) -heterocyclyl,    -   k) -alkyl,    -   l) -alkenyl,    -   m) -alkynyl,    -   n) -alkylene-aryl,    -   o) -alkylene-heteroaryl,    -   p) -alkylene-heterocyclyl,    -   q) -alkylene-cycloalkyl,    -   r) -fused cycloalkylaryl,    -   s) -fused cycloalkylheteroaryl,    -   t) -fused heterocyclylaryl,    -   u) -fused heterocyclylheteroaryl,    -   v) -alkylene-fused cycloalkylaryl,    -   w) -alkylene-fused cycloalkylheteroaryl,    -   x) -alkylene-fused heterocyclylaryl,    -   y) -alkylene-fused heterocyclylheteroaryl;    -   z) —C(O)—O-alkyl;    -   a) —C(O)—O-alkylene-aryl;    -   bb) —C(O)—NH-alkyl;    -   cc) —C(O)—NH-alkylene-aryl;    -   dd) —SO₂-alkyl;    -   ee) —SO₂-alkylene-aryl;    -   ff) —SO₂-aryl;    -   gg) —SO₂—NH-alkyl;    -   hh) —SO₂—NH— alkylene-aryl;    -   ii) —C(O)-alkyl;    -   jj) —C(O)-alkylene-aryl;    -   kk) -G₄-G₅-G₆-R₇;    -   ll) —Y₁-alkyl;    -   mm) —Y₁-aryl;    -   nn) —Y₁-heteroaryl;    -   oo) —Y₁-alkylene-aryl;    -   pp) —Y₁-alkylene-heteroaryl;    -   qq) —Y₁-alkylene-NR₉R₁₀; or    -   rr) —Y₁-alkylene-M-R₁₁;        -   wherein            -   G₄ and G₆ independently comprise alkylene, alkenylene,                alkynylene, cycloalkylene, heterocyclylene, arylene,                heteroarylene, (aryl)alkylene, (heteroaryl)alkylene,                (aryl)alkenylene, (heteroaryl)alkenylene, or a direct                bond;            -   G₅ comprises —O—, —S—, —N(R₈)—, —S(O)—, —S(O)₂—, —C(O)—,                —O—C(O)—, —C(O)—O—, —C(O)N(R₈)—, N(R₈)C(O)—,                —S(O₂)N(R₈)—, N(R₈)S(O₂)—, —O-alkylene-C(O)—,                —(O)C-alkylene-O—, —O-alkylene-, -alkylene-O—, alkylene,                alkenylene, alkynylene, cycloalkylene, heterocyclylene,                arylene, heteroarylene, fused cycloalkylarylene, fused                cycloalkylheteroarylene, fused heterocyclylarylene,                fused heterocyclylheteroarylene, or a direct bond,                wherein R_(g) comprises -hydrogen, -aryl, -alkyl,                -alkylene-aryl, or -alkylene-O-aryl;            -   R₇ comprises hydrogen, aryl, heteroaryl, cycloalkyl,                heterocyclyl, alkyl, alkenyl, alkynyl, alkylene-aryl,                -alkylene-heteroaryl, -alkylene-heterocyclyl,                -alkylene-cycloalkyl, fused cycloalkylaryl, fused                cycloalkylheteroaryl, fused heterocyclylaryl, fused                heterocyclylheteroaryl, alkylene-fused cycloalkylaryl,                -alkylene-fused cycloalkylheteroaryl, -alkylene-fused                heterocyclylaryl, or -alkylene-fused                heterocyclylheteroaryl;            -   Y₁ and W₁ independently comprise —CH₂—, —O—, —N(H), —S—,                SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -   wherein R₁₂ and R₁₃ independently comprise aryl,                    alkyl,-alkylene-aryl, alkoxy, or -alkylene-O-aryl;                    and

            -   R₉, R₁₀, and R₁₁ independently comprise aryl,                heteroaryl, alkyl, -alkylene-heteroaryl, or                -alkylene-aryl; and R₉ and R₁₀ may be taken together to                form a ring having the formula —(CH₂)_(o)—X₁—(CH₂)_(p)—                bonded to the nitrogen atom to which R₉ and R₁₀ are                attached,                -   wherein                -    o and p are, independently, 1, 2, 3, or 4; and                -    X₁ comprises a direct bond, —CH₂—, —O—, —S—,                    —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₁₄ and R₁₅ independently hydrogen, aryl,                    heteroaryl, alkyl, -alkylene-aryl, or                    -alkylene-heteroaryl;                    wherein

    -   the aryl and/or alkyl group(s) in R₁, R₂, R₃, R₄, R₅, R₆, R₇,        R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ may be optionally        substituted 1-4 times with a substituent group, wherein said        substituent group(s) or the term substituted refers to a group        comprising:        -   a) —H,        -   b) -halogen,        -   c) -hydroxyl,        -   d)-cyano,        -   e)-carbamoyl,        -   f)-carboxyl,        -   g) —Y₂-alkyl;        -   h) —Y₂-aryl;        -   i) —Y₂-heteroaryl;        -   j) —Y₂-alkylene-heteroarylaryl;        -   k) —Y₂-alkylene-aryl;        -   l) —Y₂-alkylene-W₂—R₁₅;        -   m) —Y₃—Y₄—NR₂₃R₂₄,        -   n) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄,        -   o) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, or        -   p) —Y₃—Y₄—Y₅-A₂,            -   wherein                -   Y₂ and W₂ independently comprise —CH₂—, —O—, —N(H),                    —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                    —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

-   -   -   -   -    wherein;                -    R₁₉ and R₂₀ independently comprise hydrogen, aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkylene-O-aryl;                    and                -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                    -alkylene-heteroaryl, and -alkylene-O-aryl;                -   Y₃ and Y₅ independently comprise a direct bond,                    —CH₂—, —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—,                    —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,                    —NHSO₂NH—, —O—CO—,

-   -   -   -   -    wherein R₂₇ and R₂₆ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;                -   Y₄ comprises                -    a) -alkylene;                -    b) -alkenylene;                -    c) -alkynylene;                -    d) -arylene;                -    e) -heteroarylene;                -    f) -cycloalkylene;                -    g) -heterocyclylene;                -    h) -alkylene-arylene;                -    i) -alkylene-heteroarylene;                -    j) -alkylene-cycloalkylene;                -    k) -alkylene-heterocyclylene;                -    l) -arylene-alkylene;                -    m) -heteroarylene-alkylene;                -    n) -cycloalkylene-alkylene;                -    o) -heterocyclylene-alkylene;                -    p) —O—;                -    q) —S—;                -    r) —S(O₂)—; or                -    s) —S(O)—;                -    wherein said alkylene groups may optionally contain                    one or more O, S, S(O), or SO₂ atoms;                -   A₂ comprises                -    a) heterocyclyl, fused arylheterocyclyl, or fused                    heteroarylheterocyclyl, containing at least one                    basic nitrogen atom,                -    b)-imidazolyl, or                -    c)-pyridyl; and                -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen,                    aryl, heteroaryl, -alkylene-heteroaryl, alkyl,                    -alkylene-aryl, -alkylene-O-aryl, or                    -alkylene-O-heteroaryl; and R₂₃ and R₂₄ may be taken                    together to form a ring having the formula                    —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen atom                    to which R₂₃ and R₂₄ are attached                -    wherein                -    s and t are, independently, 1, 2, 3, or 4;                -    X₃ comprises a direct bond, —CH₂—, —O—, —S—,                    —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₅ and R₂₉ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl;                    wherein

    -   either        -   at least one of the groups R₁, R₂, R₃ and R₄ are substituted            with at least one group of the formula —Y₃—Y₄—NR₂₃R₂₄,            —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, or            —Y₃—Y₄—Y₅-A₂, with the proviso that no more than one of R₂₃,            R₂₄, and R₂₅ may comprise aryl or heteroaryl;

    -   or        -   R₂ is a group of the formula

andwherein

-   -   one of R₃ and R₄, R₃ and R₂, or R₁ and R₂ may be taken together        to constitute, together with the atoms to which they are bonded,        an aryl, heteroaryl, fused arylcycloalkyl, fused        arylheterocyclyl, fused heteroarylcycloalkyl, or fused        heteroarylheterocyclyl ring system,    -   wherein        -   said ring system or R₁, R₂, R₃, or R₄ is substituted with at            least one group of the formula            -   a) —Y₅—Y₆—NR₃₃R₃₄;            -   b) —Y₅—Y₆—NH—C(═NR₃₅)NR₃₃R₃₄;            -   c) —Y₅—Y₆—C(═NR₃₅)NR₃₃R₃₄; or            -   d) —Y₅—Y₆—Y₇-A₄;            -   wherein                -   Y₅ and Y₇ independently comprise a direct bond,                    —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—,                    —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                    —O—CO—,

-   -   -   -   -    wherein R₃₆ and R₃₇ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;                -   Y₆ comprises                -    a) alkylene;                -    b) alkenylene;                -    c) alkynylene;                -    d) arylene;                -    e) heteroarylene;                -    f) cycloalkylene;                -    g) heterocyclylene;                -    h) alkylene-arylene;                -    i) alkylene-heteroarylene;                -    j) alkylene-cycloalkylene;                -    k) alkylene-heterocyclylene;                -    l) arylene-alkylene;                -    m) heteroarylene-alkylene;                -    n) cycloalkylene-alkylene;                -    j) heterocyclylene-alkylene;                -    p) —O—;                -    q) —S—;                -    r) —S(O₂)—; or                -    s)—S(O)—;                -    wherein said alkylene groups may optionally contain                    one or more O, S, S(O), or SO₂ atoms;                -   A₄ comprises                -    a) heterocyclyl, fused arylheterocyclyl, or fused                    heteroarylheterocyclyl, containing at least one                    basic nitrogen atom,                -    b) -imidazolyl, or                -    c) -pyridyl; and                -   R₃₃, R₃₄ and R₃₅ independently comprise hydrogen,                    aryl, heteroaryl, alkyl, -alkylene-aryl, or                    -alkylene-O-aryl; with the proviso that no two of                    R₃₃, R₃₄ and R₃₅ are aryl and/or heteroaryl; and R₃₃                    and R₃₄ may be taken together to form a ring having                    the formula —(CH₂)—X₄—(CH₂)_(n)— bonded to the                    nitrogen atom to which R₃₃ and R₃₄ are attached,                    wherein                -    u and v are, independently, 1, 2, 3, or 4;                -    X₄ comprises a direct bond, —CH₂—, —O—, —S—,                    —S(O₂)—, —C(O)—, —CONCH)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₃₆ and R₃₇ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl; and

        -   wherein said ring system is optionally substituted with            substituents comprising            -   a) —H;            -   b) -halogen;            -   c) -hydroxyl;            -   d) -cyano;            -   e) -carbamoyl;            -   f) -carboxyl;            -   g) —Y₈-alkyl;            -   h) —Y₈-aryl;            -   i) —Y₈-heteroaryl;            -   j) —Y₁-alkylene-aryl;            -   k) —Y₈-alkylene-heteroaryl;            -   l) —Y₈-alkylene-NR₃₈R₃₉; or            -   m) —Y₅-alkylene-W₃—R₄₀;                -   wherein                -    Y₈ and W₃ independently comprise —CH₂—, —O—, —N(H),                    —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                    —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -    wherein R₄₁ and R₄₂ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl; and                -    R₃₈, R₃₉, and R₄₀ independently comprise hydrogen,                    aryl, alkyl, -alkylene-aryl, -alkylene-heteroaryl,                    and -alkyene-O-aryl; and R₃₈ and R₃₉ may be taken                    together to form a ring having the formula                    —(CH₂)_(w)—X₇—(CH₂)_(x)— bonded to the nitrogen atom                    to which R₃₈ and R₃₉ are attached wherein                -    w and x are, independently, 1, 2, 3, or 4;                -    X₇ comprises a direct bond, —CH₂—, —O—, —S—,                    —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₄₃ and R₄₄ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl;                    or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compound of Formula (I) comprises acompound of the Formula (Ia)

wherein

-   R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl,    -heterocyclyl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl,    -alkylene-heterocyclyl, -alkylene-cycloalkyl, or -G₁-G₂-G₃-R₅    -   wherein        -   G₁ and G₃ independently comprise alkylene or a direct bond;        -   G₂ comprises —O—, —CO₂—, or a direct bond; and        -   R₅ comprises hydrogen, aryl, heteroaryl, cycloalkyl,            heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,            -alkylene-heteroaryl, -alkylene-heterocyclyl, or            -alkylene-cycloalkyl.-   R₂ comprises    -   a) -hydrogen,    -   b) -aryl,    -   c) -heteroaryl,    -   d) -heterocyclyl,    -   e) -alkyl,    -   f) -alkylene-aryl,    -   g) -alkylene-heteroaryl,    -   h) -alkylene-heterocyclyl,    -   i) -fused cycloalkylaryl,    -   j) -fused cycloalkylheteroaryl,    -   k) -fused heterocyclylaryl,    -   l) -fused heterocyclylheteroaryl;    -   m) -alkylene-fused cycloalkylaryl,    -   n) -alkylene-fused cycloalkylheteroaryl,    -   o) -alkylene-fused heterocyclylaryl,    -   p) -alkylene-fused heterocyclylheteroaryl; or    -   q) a group of the formula

-   -   -   wherein            -   A₃ comprises an aryl or heteroaryl group;            -   L₁ and L₂ independently comprise alkylene or alkenylene;            -   L₃ comprises a direct bond, alkylene, —O—, —S—, —S(O₂)—,                —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -   wherein R₃₀, R₃₁, and R₃₂ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, alkylene-aryl, or                    -alkylene-heteroaryl;

-   R₃ and R₄ independently comprise    -   a) -hydrogen;    -   b) -halogen,    -   c) -hydroxyl,    -   d) -cyano,    -   e) -carbamoyl,    -   f) -carboxyl;    -   g) -aryl,    -   h) -heteroaryl,    -   i) -cycloalkyl,    -   j) -heterocyclyl,    -   k) -alkyl,    -   l) -alkenyl,    -   m) -alkynyl,    -   n) -alkylene-aryl,    -   o) -alkylene-heteroaryl,    -   p) -alkylene-heterocyclyl,    -   q) -alkylene-cycloalkyl,    -   r) -fused cycloalkylaryl,    -   s) -fused cycloalkylheteroaryl,    -   t) -fused heterocyclylaryl,    -   u) -fused heterocyclylheteroaryl,    -   v) -alkylene-fused cycloalkylaryl,    -   w) -alkylene-fused cycloalkylheteroaryl,    -   x) -alkylene-fused heterocyclylaryl,    -   y) -alkylene-fused heterocyclylheteroaryl;    -   z) —C(O)—O-alkyl;    -   å) —C(O)—O-alkylene-aryl;    -   bb) —C(O)—NH-alkyl;    -   cc) —C(O)—NH-alkylene-aryl;    -   dd) —SO₂-alkyl;    -   ee) —SO₂-alkylene-aryl;    -   ff) SO₂-aryl;    -   gg) —SO₂—NH-alkyl;    -   hh) —SO₂—NH— alkylene-aryl    -   ii) —C(O)-alkyl;    -   jj) —C(O)-alkylene-aryl;    -   kk) -G₄-G₅-G₆-R₇    -   ll) —Y₁-alkyl;    -   mm) —Y₁-aryl;    -   nn) —Y₁-heteroaryl;    -   oo) —Y₁-alkylene-aryl;    -   pp) —Y₁-aralkylene-heteroaryl;    -   qq) —Y₁-alkylene-NR₉R₁₀; and    -   rr) —Y₁-alkylene-W₁—R₁₁;        -   wherein            -   G₄ and O₆ independently comprise alkylene, alkenylene,                alkynylene, cycloalkylene, heterocyclylene, arylene,                heteroarylene, (arylalkylene, (heteroary)alkylene,                (aryl)alkenylene, (heteroaryl)alkenylene, or a direct                bond;            -   G₅ comprises —O—, —S—, —N(R₈)—, —S(O)—, —S(O)₂—, —C(O)—,                —C(O)N(R₈)—, N(R₈)C(O)—, —S(O₂)N(R₈)—, N(R₈)S(O₂)—,                —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-,                alkylene-O—, alkylene, alkenylene, alkynylene,                cycloalkylene, heterocyclylene, arylene, heteroarylene,                fused cycloalkylaryl, fused cycloalkylheteroaryl, fused                heterocyclylaryl, fused heterocyclylheteroaryl, or a                direct bond, wherein R₈ comprises -hydrogen, -aryl,                -alkyl, -alkylene-aryl, or -alkylene-O-aryl;            -   R₇ comprises hydrogen; aryl, heteroaryl, cycloalkyl,                heterocyclyl, alkyl, alkenyl, alkynyl, alkylene-aryl,                -alkylene-heteroaryl, -alkylene-heterocyclyl,                -alkylene-cycloalkyl, fused cycloalkylaryl, fused                cycloalkylheteroaryl, fused heterocyclylaryl, fused                heterocyclylheteroaryl, alkylene-fused cycloalkylaryl,                -alkylene-fused cycloalkylheteroaryl, -alkylene-fused                heterocyclylaryl, or -alkylene-fused                heterocyclylheteroaryl;            -   Y₁ and W₁ independently comprise —CH₂—, —O—, —N(H), —S—,                SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -   wherein R₁₂ and R₁₃ independently comprise aryl,                    alkyl,-alkylene-aryl, alkoxy, or -alkylene-O-aryl;

            -   R₉, R₁₀, and R₁₁ independently comprise aryl,                heteroaryl, alkyl, -alkylene-heteroaryl, or                -alkylene-aryl; and R₉ and R₁₀ may be taken together to                form a ring having the formula —(CH₂)_(o)—X₁—(CH₂)_(p)—                bonded to the nitrogen atom to which R₉ and R₁₀ are                attached,                -   wherein                -    o and p are, independently, 1, 2, 3, or 4;                -    X₁ comprises a direct bond, —CH₂—, —O—, —S—,                    —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   with the proviso that R₃ and R₄ can not both be                hydrogen.

In one group of preferred embodiments of Formula (Ia), R₁ comprises ahydrogen, methyl, ethyl, propyl, butyl, iso-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 3-butenyl, tert-butyl,3-cyclohexyl-propyl, 3-phenoxy-propyl, methoxymethyl, 4-fluoro-phenyl,3-(4-chlorophenoxy)-propyl, 2,4,4-trimethyl-pentyl, 1-ethyl-propyl,1-propyl-butyl, benzyloxymethyl, 2-cyclopropy-ethyl, 2-phenyl-ethyl,4-tert-butylphenoxymethyl, 4-tert-butylcyclohexyl, 4-butylcyclohexyl ,4-ethylcyclohexyl, 3-methoxycarbonyl-1-propyl, or 2-(pyridin-3-yl)-ethylgroup.

In another group of preferred embodiments of Formula (Ia), R₂ comprisesa phenyl or 1,2,3,4-tetrahydroisoquinoline group, wherein the phenylgroup is substituted with at least one substitutent comprising

-   -   a) —Y₂-alkyl;    -   b) —Y₂-aryl;    -   c) —Y₂-heteroaryl;    -   d) —Y₂-alkylene-heteroarylaryl;    -   e) —Y₂-alkylene-aryl; —Y₂-alkylene-W₂—R₁₈;    -   g) —Y₃—Y₄—NR₂₃R₂₄;    -   h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄;    -   i) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄; or    -   j) —Y₃—Y₄—Y₅-A₂;        -   wherein            -   Y₂ and W₂ independently comprise —CH₂— or —O—, and            -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                -alkylene-heteroaryl, or -alkylene-O-aryl;            -   Y₃ and Y₅ independently comprise a direct bond, —CH₂—,                —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—,                —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                -   a) -alkylene;                -   b) -alkenylene;                -   c) -alkynylene;                -   d) -arylene;                -   e) -heteroarylene;                -   f) -cycloalkylene;                -   g) -heterocyclylene;                -   h) -alkylene-arylene;                -   i) -alkylene-heteroarylene;                -   j) -alkylene-cycloalkylene;                -   k) -alkylene-heterocyclylene;                -   l) -arylene-alkylene;                -   m) -heteroarylene-alkylene;                -   n) -cycloalkylene-alkylene;                -   t) -heterocyclylene-alkylene;                -   u) —O—;                -   v) —S—;                -   w) —S(O₂)—; or                -   x) —S(O)—;                -    wherein said alkylene groups may optionally contain                    one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                -   a) heterocyclyl, fused arylheterocyclyl, or fused                    heteroarylheterocyclyl, containing at least one                    basic nitrogen atom,                -   b) -imidazolyl, or                -   c) -pyridyl; and

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                R₂₄ may be taken together to form a ring having the                formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                atom to which R₂₃ and R₂₄ are attached                -   wherein                -    s and t are, independently, 1, 2, 3, or 4;                -    X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                    —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                    —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl.

In another group of preferred embodiments of compounds of Formula (Ia),R₂ comprises 4-[3-(N,N′-diethylamino)-propoxy]-phenyl,4-[3-(N,N′-dimethylamino)-propoxy]-phenyl,3-[3-(N,N′-diethylamino)-propoxy]-phenyl,4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl,4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl,4-(4-trifluoromethoxy-phenoxy)-phenyl, 4-(3,4-dichloro-phenoxy)-phenyl,4-(3,5-bis-trifluoromethyl-phenoxy)-phenyl, 4-benzyloxy-phenyl,4-(4-methyloxy-phenoxy)-phenyl, 4-(2-hexyl-4-chloro-phenoxy)-phenyl,4-(4-phenyl-phenoxy)-phenyl, 4-(4-acetamido-phenoxy)-phenyl,4-(4-methyl-phenoxy)-phenyl, 4-(4-fluoro-phenoxy)-phenyl,4-(4-bromo-phenoxy)-phenyl, 4-(4-chloro-phenoxy)-phenyl,4-(4-amino-phenoxy)-phenyl, 4-(3-ethyl-4-chloro-phenoxy)-phenyl,4-[2-(N-ethylamino)-ethoxy]-phenyl,4-[2,2′-dimethyl-3-(N,N′-dimethylamino)-propoxy]-phenyl,1,2,3,4-tetrahydroisoquinolin-7-yl, 4-(4-benzamido-phenoxy)-phenyl,4-(4-isonicotinamido-phenoxy)-phenyl,4-[2-(N-methyl-N′-pyrid-4-yl)-ethoxy]-phenyl, 4-[3-(diethylmethylammonium)-propoxy)]-phenyl, 4-(2,5-di-fluoro-benzyloxy)-phenyl,4-(2,4-dichloro-phenoxy)-phenyl, 4-(naphthalen-2-yloxy)-phenyl,4-(6-methoxy-naphthalen-2-yloxy)-phenyl,4-(4-methoxy-naphthalen-2-yloxy)-phenyl,4-(6-hydroxy-naphthalen-2-yloxy)-phenyl,4-(dibenzofuran-2-yloxy)-phenyl,4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl,4-[2-(piperazin-1-yl)-ethoxy]-phenyl, or4-(4-tert-butyl-phenoxy)-phenyl.

In another group of preferred embodiments of Formula (Ia), R₃ compriseshydrogen; and R₄ comprises a phenyl group, wherein the phenyl group issubstituted with at least one substituent comprising

-   -   a) —Y₂-alkyl;    -   b) —Y₂-aryl;    -   c)—Y₂-heteroaryl;    -   d) —Y₂-alkylene-heteroarylaryl;    -   e)—Y₂-alkylene-aryl;    -   f) —Y₂-alkylene-W₂—R₁₈;    -   g) —Y₃—Y₄—NR₂₃R₂₄;    -   h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄;    -   i) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄; or    -   j) —Y₃—Y₄—Y₅-A₂;        -   wherein            -   Y₂ and W₂ independently comprise —CH₂— or —O—;            -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                -alkylene-heteroaryl, or -alkylene-O-aryl;            -   Y₃ and Y₅ independently comprise a direct bond, —CH₂—,                —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—,                —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                -   a) -alkylene;                -   b) -alkenylene;                -   c) -alkynylene;                -   d) -arylene;                -   e) -heteroarylene;                -   f) -cycloalkylene;                -   g) -heterocyclylene;                -   h) -alkylene-arylene;                -   i) -alkylene-heteroarylene;                -   j) -alkylene-cycloalkylene;                -   k) -alkylene-heterocyclylene;                -   l)-arylene-alkylene;                -   m) -heteroarylene-alkylene;                -   n) -cycloalkylene-alkylene;                -   o) -heterocyclylene-alkylene;                -   p) —O—;                -   q) —S—;                -   r) —S(O₂)—; or                -   s) —S(O)—;                -    wherein said alkylene groups may optionally contain                    one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                -   a) heterocyclyl, fused arylheterocyclyl, or fused                    heteroarylheterocyclyl, containing at least one                    basic nitrogen atom,                -   b) -imidazolyl, or                -   c) -pyridyl;

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                R₂₄ may be taken together to form a ring having the                formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                atom to which R₂₃ and R₂₄ are attached                -   wherein                -    s and t are, independently, 1, 2, 3, or 4;                -    X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                    —C(O)—, CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                    —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl.

In a more preferred group of compounds of Formula (Ia), R₃ compriseshydrogen and R₄ comprises 4-{2-[(4-chlorophenyl)-ethoxy]}-phenyl,4-[3-(N,N′-diethylamino)-propoxy]-phenyl, 4-(2-amino-ethoxy)-phenyl,4-[2-(N-methyl-N′-pyridin-4-yl-amino)-ethoxy]-phenyl,4-[2-(N-ethyl-N′-pyridin-4-yl-amino)-ethoxy]-phenyl,4-[2-(N-pyridin-4-yl-amino)-ethoxy]-phenyl,4-(4-amino-pyridin-3-yl-oxy)-phenyl, 4-[(pyridin-4-yl)-amino]-phenyl,4-[2-(N,N′-bis-pyridin-2-ylmethyl-amino)-ethoxy]-phenyl,4-[2-(guanidinyl)-ethoxy]-phenyl,4-{2-[4-(pyridin-4-yl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl,4-[2-(N-methyl-N′-3-methylpyridin-4-yl-amino)-ethoxy]-phenyl,4-(4-hydroxy-pyrrolidin-2-ylmethyloxy)-phenyl,4-(4-amino-3,5-dimethyl-pyrrolidin-2-ylmethyloxy)-phenyl,dibenzofuran-2-yl, 4-[3-(piperazin-1-yl)-propoxy]-phenyl,4-(piperazin-4-yloxy)-phenyl, 4-[5-(piperazin-1-yl)-pentoxy]-phenyl,4-[3-(N,N′-dimethylamino)-propoxy]-phenyl,4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl,4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl,4-(4-phenyl-phenoxy)-phenyl, 4-(3-trifluoromethoxy-phenoxy)-phenyl,4-(4-trifluoromethyl-benzyloxy)-phenyl, 4-(3,4-dichloro-phenoxy)-phenyl,4-(2,4-dichloro-phenoxy)-phenyl, 4-(1-ethyl-piperidin-3-yloxy)-phenyl,4-benzyloxy-phenyl, 4-[(1-ethyl-piperidin-3-yl)-methoxy]-phenyl,4-(4-phenoxy-benzyloxy)-phenyl, 4-(4-benzyloxy-benzyloxy)-phenyl,4-(2-benzenesulfonylmethyl-benzyloxy)-phenyl,4-(3,4,5-trimethoxybenzoyloxy)-phenyl,4-[2-(pyrrolidin-1-yl)-ethoxy]-phenyl,442-(piperidin-1-yl)-ethoxy]-phenyl,4-[2,2′-dimethyl-3-(N,N′-dimethylamino)-propoxy]-phenyl,4-[2-(N,N′-diisopropylamino)-ethoxy]-phenyl,4-(adamantan-1-ylmethoxy)-phenyl,3-[(2,6-dichlorophenyl)-4-methyl-isoxazol-5-ylmethyloxy]-phenyl,4-(4-bromo-benzyloxy)-phenyl, 4-(4-chlorophenoxy)-phenyl,4-[4-{(1-ethyl-piperidin-4-yl)-methylamino}-phenoxy]-phenyl,4-(3,3-diphenylpropoxy)-phenyl,4-[3,3-Bis-(4-fluorophenyl)-propoxy]-phenyl,4-[3,3-Bis-(4-chlorophenyl)-allyoxy]-phenyl,4-(4-chlorophenoxy)-naphthalenyl,4-[2-(biphenyl-4-yl)-acetamido]-phenyl,4-(2-(9H-carbazole)-ethoxy]-phenyl, 4-[4-methoxyphenyoxy]-phenyl,4-(4-tert-butyl-phenoxy)-phenyl, or 4-(naphthylen-2-ylmethoxy)-phenyl.

In another preferred embodiment, the compound Formula (I) comprises thecompound of Formula (Ib),

wherein

-   -   R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl,        -heterocyclyl, -alkyl, -alkenyl, -alkylene-aryl,        -alkylene-heteroaryl, -alkylene-heterocyclyl,        -alkylene-cycloalkyl, -fused cycloalkylaryl, -fused        cycloalkylheteroaryl, -fused heterocyclylaryl, -fused        heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl,        -alkylene-fused cycloalkylheteroaryl, -alkylene-fused        heterocyclylaryl, -alkylene-fused heterocyclylheteroaryl, or        -G₁-G₂-G₃-R₅        -   wherein            -   G₁ and G₃ independently comprise alkylene, alkenylene,                alkynylene, cycloalkylene, heterocyclylene, arylene,                heteroarylene, (aryl)alkylene, (heteroaryl)alkylene,                (aryl)alkenylene, (heteroaryl)alkenylene, or a direct                bond;            -   G₂ comprises —O—, —S—, —S(O)—, —N(R₆)—, —S(O)₂—, —C(O)—,                —CO₂—, —C(O)N(R₆)—, N(R₆)C(O)—, —S(O₂)N(R₆)—,                N(R₆)S(O₂)—, —O-alkylene-C(O)—, —(O)C-alkylene-O—,                —O-alkylene-, -alkylene-O—, alkylene, alkenylene,                alkynylene, cycloalkylene, heterocyclylene, arylene,                heteroarylene, fused cycloalkylaryl, fused                cycloalkylheteroaryl, fused heterocyclylaryl, fused                heterocyclylheteroaryl, or a direct bond, wherein R₆                comprises hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy,                or -alkylene-O-aryl; and            -   R₅ comprises hydrogen, aryl, heteroaryl, cycloalkyl,                heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,                -alkylene-heteroaryl, -alkylene-heterocyclyl,                -alkylene-cycloalkyl, fused cycloalkylaryl, fused                cycloalkylheteroaryl, fused heterocyclylaryl, fused                heterocyclylheteroarylalkylene-fused cycloalkylaryl,                -alkylene-fused cycloalkylheteroaryl, -alkylene-fused                heterocyclylaryl, or -alkylene-fused                heterocyclylheteroaryl;    -   R₃ comprises hydrogen or an alkyl group; and    -   R₁₀₂ and R₁₀₄ independently comprise        -   a) —H;        -   b) -alkyl;        -   c) -aryl;        -   d) -heteroaryl;        -   e) -alkylene-heteroarylaryl;        -   f) -alkylene-aryl;        -   g) -alkylene-W₂—R₁₆;        -   h) —Y₄—NR₂₃R₂₄;        -   l) —Y₄—NH—C(═NR₂₅)NR₂₃R₂₄;        -   j) —Y₄—C(═NR₂₅)NR₂₃R₂₄; or        -   k) —Y₄—Y₅-A₂;            -   wherein                -   W₂ comprises —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—,                    —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,                    —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

-   -   -   -   -    wherein R₁₉ and R₂₀ independently comprise                    hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy, or                    -alkylene-O-aryl; and                -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                    -alkylene-heteroaryl, and -alkylene-O-aryl;                -   Y₅ comprises a direct bond, —CH₂—, —O—, —N(H), —S—,                    SO₂—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -    wherein R₂₇ and R₂₆ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;                -   Y₄ comprises                -    a) -alkylene;                -    b) -alkenylene;                -    c) -alkynylene;                -    d) -arylene;                -    e) -heteroarylene;                -    f) -cycloalkylene;                -    g) -heterocyclylene;                -    h) -alkylene-arylene;                -    i) -alkylene-heteroarylene;                -    j) -alkylene-cycloalkylene;                -    k) -alkylene-heterocyclylene;                -    l) -arylene-alkylene;                -    m) -heteroarylene-alkylene;                -    n) -cycloalkylene-alkylene;                -    o) -heterocyclylene-alkylene;                -    p) —O—;                -    q) —S—;                -    r) —S(O₂)—; or                -    s) —S(O)—;                -    wherein said alkylene groups may optionally contain                    one or more O, S, S(O), or SO₂ atoms;                -   A₂ comprises                -    a) heterocyclyl, fused arylheterocyclyl, or fused                    heteroarylheterocyclyl, containing at least one                    basic nitrogen atom,                -    b) -imidazolyl, or                -    c) -pyridyl;                -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen,                    aryl, heteroaryl, -alkylene-heteroaryl, alkyl,                    -alkylene-aryl, -alkylene-O-aryl, or                    -alkylene-O-heteroaryl; and R₂₃ and R₂₄ may be taken                    together to form a ring having the formula                    —(CH₂)_(s)—X₃—(CH₂)_(r) bonded to the nitrogen atom                    to which R₂₃ and R₂₄ are attached                -    wherein                -    s and t are, independently, 1, 2, 3, or 4;                -    X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                    —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                    —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl;

    -   wherein        -   the alkyl and/or aryl groups of R₁₀₂ and R₁₀₄ may be            optionally substituted 1-4 times with a substituent group,            wherein said substituent group(s) or the term substituted            refers to a group comprising:            -   a) halogen;            -   b) perhaloalkyl;            -   c) alkyl;            -   d) cyano;            -   e) alkyloxy;            -   f) aryl; or            -   g) aryloxy.

In a group of preferred embodiments of the compound of Formula (Ib), R₁comprises a hydrogen, methyl, ethyl, propyl, butyl, iso-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-butenyl, tert-butyl,3-cyclohexyl-propyl, 3-phenoxy-propyl, methoxymethyl, 4-fluoro-phenyl,3-(4-chlorophenoxy)-propyl, 2,4,4-trimethyl-pentyl, 1-ethyl-propyl,1-propyl-butyl, benzyloxymethyl, 2-cyclopropy-ethyl, 2-phenyl-ethyl,4-tert-butylphenoxymethyl, 4-tert-butylcyclohexyl, 4-ethylcyclohexyl,4-butylcyclohexyl, 3-methoxycarbonyl-1-propyl, or 2-(pyridin-3-yl)-ethylgroup, and R₃ comprises hydrogen.

In another group of preferred embodiments of the compound of Formula(Ib), R₁₀₂ and R₁₀₄ independently comprise 2-(4-chlorophenyl)-ethyl,3-(N,N′-diethylamino)-propyl, 2-amino-ethyl,2-(N-methyl-N′-pyridin-4-yl-amino)-ethyl,2-(N-ethyl-N′-pyridin-4-yl-amino)-ethyl,2-(N-pyridin-4-yl-amino)-ethoxy, 4-(4-amino-pyridin-3-yl-oxy),4-(pyridin-4-yl)-amino, 2-(N,N′-bis-pyridin-2-ylmethyl-amino)-ethyl,2-(guanidinyl)-ethyl, 2-[4-(pyridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl,2-(N-methyl-N′-3-methylpyridin-4-yl-amino)-ethyl,4-hydroxy-pyrrolidin-2-ylmethyl,4-amino-3,5-dimethyl-pyrrolidin-2-ylmethyl, dibenzofuran-2-yl,3-(piperazin-1-yl)-propyl, piperazin-4-yl, 5-(piperazin-1-yl)-pentyl,3-(N,N′-dimethylamino)-propyl, 3-fluoro-4-trifluoromethyl-phenyl,4-fluoro-3-trifluoromethyl-phenyl, 4-phenyl-phenyl,3-trifluoromethoxy-phenyl, 4-trifluoromethyl-benzyl,3,4-dichloro-phenyl, 2,4-dichloro-phenyl, 1-ethyl-piperidin-3-yl,benzyl, (1-ethyl-piperidin-3-yl)-methyl, 4-phenoxy-benzyl,4-benzyloxy-benzyl, 2-benzenesulfonylmethyl-benzyl,3,4,5-trimethoxybenzyl, 2-(pyrrolidin-1-yl)-ethyl,2-(piperidin-1-yl)-ethyl, 2,2′-dimethyl-3-(N,N′-dimethylamino)-propyl,2-(N,N′-diisopropylamino)-ethyl,3-(2,6-dichlorophenyl)-4-methyl-isoxazol-5-ylmethyl, 4-bromo-benzyl,4-chlorophenyl, 4-{(1-ethyl-piperidin-4-yl)-methylamino}-phenyl,3,3-diphenylpropyl, 3,3-Bis-(4-fluorophenyl)-propyl,3,3-Bis-(4-chlorophenyl)-allyl, 4-(4-chlorophenoxy)-naphthalenyl,4-[2-(biphenyl-4-yl)-acetamido]-phenyl, 2-(9H-carbazole)-ethyl,4-methoxyphenyl, 4-tert-butyl-phenyl, or naphthylen-2-ylmethyl.

In another group of preferred embodiments of the compound of Formula(Ib), R₁ comprises -alkyl, -alkylene-cycloalkylene-alkyl, -cycloalkyl,-heterocyclyl, -alkylene-cycloalkyl, -alkylene-heteroaryl,-alkylene-heterocyclyl, or -alkylene-heterocyclylene-alkyl; R₃ compriseshydrogen; R₁₀₂ comprises -aryl or -alkylene-aryl substituted with atleast one of a halogen, a perhaloalkyl, or an alkoxy group; and R₁₀₄comprises —Y₄—NR₂₃R₂₄ or —Y₄—Y₅-A₂.

In another group of preferred embodiments of the compound of Formula(Ib), R₁ comprises -heterocyclyl, heterocyclylene-heteroaryl,-alkylene-cycloalkyl, -alkylene-heteroaryl, -alkylene-heterocyclyl, or-alkylene-heterocyclylene-alkyl; R₃ comprises hydrogen; and R₁₀₂ andR₁₀₄ independently comprise -aryl or -alkylene-aryl, wherein the alkylor ary groups are optionally substituted with at least one of a halogen,a perhaloalkyl, or an alkoxy group, and wherein at least one of R₁₀₂ andR₁₀₄ comprise —Y₄—NR₂₃R₂₄ or —Y₄—Y₅-A₂, wherein Y₄ comprises alkylene.

In a preferred embodiment, the compound of Formula (I) comprises acompound of the Formula (Ic)

wherein

-   -   R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl,        -heterocyclyl, -alkyl, -alkenyl, -alkynyl, -alkylene-aryl,        -alkylene-heteroaryl, -alkylene-heterocyclyl,        -alkylene-cycloalkyl, -fused cycloalkylaryl, -fused        cycloalkylheteroaryl, -fused heterocyclylaryl, -fused        heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl,        -alkylene-fused cycloalkylheteroaryl, -alkylene-fused        heterocyclylaryl, -alkylene-fused heterocyclylheteroaryl, or        -G₁-G₂-G₃-R₅        -   wherein            -   G₁ and G₃ independently comprise alkylene, alkenylene,                alkynylene, cycloalkylene, heterocyclylene, arylene,                heteroarylene, (aryl)alkylene, (heteroaryl)alkylene,                (aryl)alkenylene, (heteroaryl)alkenylene, or a direct                bond;            -   G₂ comprises —O—, —S—, —S(O)—, —N(R₆)—, —S(O)₂—, —C(O)—,                —CO₂—, —C(O)N(R₆)—, N(R₆)C(O)—, —S(O₂)N(R₆)—,                N(R₆)S(O₂)—, —O-alkylene-C(O)—, —(O)C-alkylene-O—,                —O-alkylene-, -alkylene-O—, alkylene, alkenylene,                alkynylene, cycloalkylene, heterocyclylene, arylene,                heteroarylene, fused cycloalkylaryl, fused                cycloalkylheteroaryl, fused heterocyclylaryl, fused                heterocyclylheteroaryl, or a direct bond, wherein R₆                comprises hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy,                or -alkylene-O-aryl; and            -   R₆ comprises hydrogen, aryl, heteroaryl, cycloalkyl,                heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,                -alkylene-heteroaryl, -alkylene-heterocyclyl,                -alkylene-cycloalkyl, fused cycloalkylaryl, fused                cycloalkylheteroaryl, fused heterocyclylaryl, fused                heterocyclylheteroaryl; -alkylene-fused cycloalkylaryl,                -alkylene-fused cycloalkylheteroaryl, -alkylene-fused                heterocyclylaryl, or -alkylene-fused                heterocyclylheteroaryl;    -   R₂ comprises        -   a) -hydrogen,        -   b) -aryl,        -   c) -heteroaryl,        -   d) -cycloalkyl,        -   e) -heterocyclyl;        -   f) -alkyl,        -   g) -alkenyl,        -   h) -alkynyl,        -   i) -alkylene-aryl,        -   j) -alkylene-heteroaryl,        -   k) -alkylene-heterocyclyl,        -   l) -alkylene-cycloalkyl;        -   m) fused cycloalkylaryl,        -   n) fused cycloalkylheteroaryl,        -   o) fused heterocyclylaryl,        -   p) fused heterocyclylheteroaryl;        -   q) -alkylene-fused cycloalkylaryl,        -   r) -alkylene-fused cycloalkylheteroaryl,        -   s) -alkylene-fused heterocyclylaryl, or        -   t) -alkylene-fused heterocyclylheteroaryl,    -   R₁₁₁, R₁₁₂, R₁₁₃ and R₁₁₄ independently comprise        -   a) -hydrogen,        -   b) -halogen,        -   c) -hydroxyl,        -   d) -cyano,        -   e) -carbamoyl,        -   f) -carboxyl,        -   g) —Y₈-alkyl,        -   h) —Y₈-aryl,        -   i) —Y₈-heteroaryl,        -   j) —Y₈-alkylene-aryl,        -   k) —Y₈-alkylene-heteroaryl,        -   l) —Y₈-alkylene-W₃—R₄₀,        -   m) —Y₅—Y₆—NR₃₃R₃₄,        -   n) —Y₈—Y₈—NH—C(═NR₃₅)NR₃₃R₃₄,        -   o) —Y₅—Y₆—C(═NR₃₅)NR₃₃R₃₄, or        -   l) —Y₅—Y₆—Y₇-A₄;            -   wherein                -   Y₅ and Y₇ independently comprise a direct bond,                    —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—,                    —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                    —O—CO—,

-   -   -   -   -    wherein R₃₆ and R₃₇ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;                -   Y₆ comprises                -    a) alkylene;                -    b) alkenylene;                -    c) alkynylene;                -    d) arylene;                -    e) heteroarylene;                -    f) cycloalkylene;                -    g) heterocyclylene;                -    h) alkylene-arylene;                -    i) alkylene-heteroarylene;                -    j) alkylene-cycloalkylene;                -    k) alkylene-heterocyclylene;                -    l) arylene-alkylene;                -    m) heteroarylene-alkylene;                -    n) cycloalkylene-alkylene;                -    o) heterocyclylene-alkylene;                -    p) —O—;                -    q) —S—;                -    r) —S(O₂)—; or s) —S(O)—;                -    wherein said alkylene groups may optionally contain                    one or more O, S, S(O), or SO₂ atoms;                -   A₄ comprises                -    a) heterocyclyl, fused arylheterocyclyl, or fused                    heteroarylheterocyclyl, containing at least one                    basic nitrogen atom,                -    b) -imidazolyl, or                -    c) -pyridyl;                -   R₃₃, R₃₄ and R₃₅ independently comprise hydrogen,                    aryl, heteroaryl, alkyl, -alkylene-aryl, or                    -alkylene-O-aryl; and R₃₃ and R₃₄ may be taken                    together to form a ring having the formula                    —(CH₂)_(n)—X₄—(CH₂)_(v)— bonded to the nitrogen atom                    to which R₃₃ and R₃₄ are attached,                -    wherein                -    u and v are, independently, 1, 2, 3, or 4;                -    X₄ comprises a direct bond, —CH₂—, —O—, —S—,                    —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                    —NHSO₂—, —SO₂N(H)—, C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₃₆ and R₃₇ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl;                -   Y₅ and W₃ independently comprise —CH₂—, —O—, —N(H),                    —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                    —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -    wherein R₄₁ and R₄₂ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl; and                -   R₄₀ comprises hydrogen, aryl, alkyl, -alkylene-aryl,                    -alkylene-heteroaryl, and -alkyene-O-aryl;

    -   wherein at least one of R₁₁₁, R₁₁₂, R₁₁₃, and R₁₁₄ comprise a        group of the formula —Y₅—Y₆—NR₃₃R₃₄, —Y₅—Y₆—NH—C(═NR₃₅)NR₃₃R₃₄,        —Y₅—Y₆—C(═NR₃₅)NR₃₃R₃₄, or —Y₅—Y₆

In one group of preferred embodiments of the compound of Formula (Ic),R₂ comprises hydrogen or alkyl.

In another group of preferred embodiments of the compound of Formula(Ic), R₁ comprises a phenyl group substituted by one or moresubstituents comprising

-   -   a) —Y₂-alkyl;    -   b) —Y₂-aryl;    -   c)—Y₂-heteroaryl;    -   d) —Y₂-alkylene-heteroarylaryl;    -   e)—Y₂-alkylene-aryl;    -   f) —Y₂-alkylene-W₂—R₁₈;    -   g) —Y₃—Y₄—NR₂₃R₂₄    -   h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄    -   i) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄    -   j) —Y₃—Y₄—Y₅-A₂        -   wherein            -   Y₂ and W₂ independently comprise —CH₂—, —O—, and            -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                -alkylene-heteroaryl, or -alkylene-O-aryl;            -   Y₃ and Y₅ independently comprise a direct bond, —CH₂—,                —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—,                —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                    alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                -   a) -alkylene;                -   b) -alkenylene;                -   c) -alkynylene;                -   d) -arylene;                -   e) -heteroarylene;                -   f) -cycloalkylene;                -   g) -heterocyclylene;                -   h) -alkylene-arylene;                -   i) -alkylene-heteroarylene;                -   j) -alkylene-cycloalkylene;                -   k) -alkylene-heterocyclylene;                -   l) -arylene-alkylene;                -   m) -heteroarylene-alkylene;                -   n) -cycloalkylene-alkylene;                -   o) -heterocyclylene-alkylene;                -   p) —O—;                -   q) —S—;                -   r) —S(O₂)—; or                -   s) —S(O)—;                -    wherein said alkylene groups may optionally contain                    one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                -   a) heterocyclyl, fused arylheterocyclyl, or fused                    heteroarylheterocyclyl, containing at least one                    basic nitrogen atom,                -   b) -imidazolyl, or                -   c) -pyridyl;

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                R₂₄ may be taken together to form a ring having the                formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                atom to which R₂₃ and R₂₄ are attached                -   wherein                -    s and t are, independently, 1, 2, 3, or 4;                -    X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                    —C(O)—, —CONCH)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                    —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                    hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                    or -alkylene-heteroaryl.

In another group of preferred embodiments of the compound of Formula(Ic), R₁ comprises 2-methoxy-3,5-dimethyoxy-phenyl,3-(4-tert-butyl-phenoxy)-phenyl,4-[3-(N,N′-diethylamino)-propoxy]-phenyl,4-[3-(N,N′-dimethylamino)-propoxy]phenyl,4-[(pyrrolidin-1-yl)-ethoxy]-phenyl,3-[(pyrrolidin-1-yl)-ethoxy]-phenyl, 2-[(pyrrolidin-1-yl)-ethoxy]phenyl,3-(naphthalen-2-yloxy)-phenyl, 4-biphenyl,3-(3,3-dimethylbutoxy)-phenyl, 3-(phenoxy)-phenyl,3-(3,4-dichloro-phenoxy)-phenyl, 3-(3,5-dichloro-phenoxy)-phenyl,4-tert-butyl-phenyl, 4-(dibutylamino)-phenyl,4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl, 2-naphthyl, 2-benzofuranyl,3-(3-trifluoromethyl-phenoxy)-phenyl, 4-chloro-phenyl, 2-benzhydryl,4-isopropoxy-phenyl, 3-(4-tertbutyl-phenoxy)-phenyl,4-[2-(4-chloro-phenyl)-ethoxy]-phenyl,3-[2-(4-chloro-phenyl)-ethoxy]-phenyl,2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl)-ethyl,2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl.

In another group of preferred embodiments of the compound of Formula(Ic), R₁ comprises 4-[2-(4-chloro-phenyl)-ethoxy]-phenyl,3-[2-(4-chloro-phenyl)-ethoxy]-phenyl,2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-ethyl,2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl.

In another group of preferred embodiments of the compound of Formula(Ic), R₁₁₁, R₁₁₂ and R₁₁₄ comprise hygrogen; and R₁₁₃ comprises—Y₃—Y₄—NR₂₃R₂₄, or —Y₃—Y₄—Y₅-A₂.

In another group of preferred embodiments of the compound of Formula(Ic), R₁ comprises 4-[2-(4-chloro-phenyl)-ethoxy]-phenyl,3-[2-(4-chloro-phenyl)-ethoxy]-phenyl,2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-ethyl,2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl;R₂ comprises alkyl; R₁₁₂ and R₁₁₄ comprise hygrogen; and R₁₁₁ and R₁₁₃comprise —Y₃—Y₄—NR₂₃R₂₄, or —Y₃—Y₄—Y₅-A₂.

In the compounds of Formula (I), the various functional groupsrepresented should be understood to have a point of attachment at thefunctional group having the hyphen. In other words, in the case of —C₁₋₆alkylaryl, it should be understood that the point of attachment is thealkyl group; an example would be benzyl. In the case of a group such as—C(O)—NH—C₁₋₆ alkylaryl, the point of attachment is the carbonyl carbon.

Also included within the scope of the invention are the individualenantiomers of the compounds represented by Formula (I) above as well asany wholly or partially racemic mixtures thereof. The present inventionalso covers the individual enantiomers of the compounds represented bythe Formula above as mixtures with diastereoisomers thereof in which oneor more stereocenters are inverted.

Compounds of the present invention preferred for their high biologicalactivity are listed by name below in Table 1.

TABLE 1 Ex. Structure Name  1

1-butyl-2-(3-cyclohexylmethoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  2

{3-[3-butyl-2-(3,5-di-tert-butyl- 2-methoxy-phenyl)-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine  3

(2-{3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-ethyl)- diisopropyl-amine  4

(3-{4-[1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine  5

1-butyl-6-(4-tert-butyl-phenoxy)- 2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole  6

1-butyl-6-(4-tert-butyl-phenoxy)- 2-[2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole  7

1-butyl-2-[3-(naphthalen-2- yloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  8

2-biphenyl-4-yl-1-butyl-6-(2- piperazin-1-yl-ethoxy)-1H- benzimidazole 9

1-butyl-6-(4-tert-butyl-phenoxy)- 2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole  10

1-butyl-2-[3-(3,3-dimethyl- butoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  11

1-butyl-6-(4-fluoro-3- trifluoromethyl-phenoxy)-2-[4-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-benzimidazole  12

1-butyl-2-(3-phenoxy-phenyl)-6- (2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  13

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H-benzimidazole  14

1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H-benzimidazole  15

1-butyl-6-[2-(4-chloro-phenyl)- ethoxy]-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzimidazole  16

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-piperidin-1-yl-ethoxy)- 1H-benzimidazole  17

1-butyl-2-(4-tert-butyl-phenyl)-6- (2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  18

dibutyl-{4-[1-butyl-6-(3- diethylamino-propoxy)-1H-benzimidazol-2-yl]-phenyl}- amine  19

(2-{3-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-ethyl)- diisopropyl-amine  20

{3-[3-butyl-2-(4-tert-butyl- phenyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine  21

1-butyl-2-(3,5-di-tert-butyl-2- methoxy-phenyl)-6-(2-piperazin-1-ylethoxy)-1H-benzoimidazole  22

{3-[3-butyl-2-(3-{4-[2-(4- methoxy-phenyl)-ethoxy]- phenyl}-propyl)-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine  23

1-butyl-2-naphthalen-2-yl-6-(2- piperazin-1-yl-ethoxy)-1H- benzimidazole 24

(2-{3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-ethyl)- dimethyl-amine  25

2-benzofuran-2-yl-1-butyl-6-(2- piperazin-1-yl-ethoxy)-1H- benzimidazole 26

1-butyl-6-(2-piperazin-1-yl- ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzimidazole  27

2-benzhydryl-1-butyl-6-(2- piperazin-1-yl-ethoxy)-1H- benzimidazole  28

1-Butyl-2-(4-chloro-phenyl)-6- (2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  29

{3-[3-Butyl-2-(4-isopropoxy- phenyl)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine  30

1-Butyl-6-(2-piperazin-1-yl- ethoxy)-2-[3-(4,4,4-trifluoro-butoxy)-phenyl]-1H- benzoimidazole  31

{3-[3-Butyl-2-(2,4,4-trimethyl- pentyl)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine  32

Diethyl-{2-[2-piperidin-3-yl-3- (4-pyrrolidin-1-yl-butyl)-3H-benzoimidazol-5-yloxy]-ethyl}-amine  33

Diethyl-{2-[2-piperidin-4-yl-3- (4-pyrrolidin-1-yl-butyl)-3H-benzoimidazol-5-yloxy]-ethyl}-amine  34

{3-[1-Butyl-6-(3-diethylamino- propoxy)-2-piperidin-4-yl-1H-benzoimidazol-4-yloxy]-propyl)- diethyl-amine  35

{3-[3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine 36

1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole  37

1-butyl-2-[3-(3-tert-butyl- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  38

2-[3-(biphenyl-4-yloxy)-phenyl]- 1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  39

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole  40

[3-(3-butyl-2-{3-[2-(4-chloro- phenyl)-ethoxy]-4-nitro-phenyl}-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine  41

[2-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-ethyl]- diethyl-amine  42

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(piperidin-4-ylmethoxy)-1H-benzoimidazole  43

1-butyl-2-{3-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole  44

{3-[3-butyl-2-(2-{4-[2-(4- chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine  45

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole  46

1-butyl-6-[2-(4-butyl-piperazin- 1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole  47

{3-[3-butyl-2-(2-{4-[2-(4- chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine  48

(3-{3-butyl-2-[3-(4-methoxy- phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)- diethyl-amine  49

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-diethylamino-ethoxy)- benzimidazol-1-yl)-propyl}- diethyl-amine  50

[3-(1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-1H-benzimidazol-4-yloxy)-propyl]- diethyl-amine  51

[3-(1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-1H-benzimidazol-5-yl)-propyl]- diethyl-amine  52

1-butyl-2-[3-(2-isopropyl- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  53

{3-[3-butyl-2-(2-{4-[3-(4- methoxy-phenyl)-propoxy]- phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine  54

{3-[3-butyl-2-(2-{4-[4-(4- methoxy-phenyl)-butoxy]- phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine  55

[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-3-ethoxy-phenyl}-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine  56

(3-{3-butyl-2-[3-(3- trifluoromethyl-phenoxy)- phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine  57

1-butyl-2-[3-(4-chloro-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  58

1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  59

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(piperidin-4-yloxy)-1H- benzoimidazole  60

3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-benzoimidazol-5-yloxy)-1-aza- bicyclo[2.2.2]octane  61

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2,2,6,6,-tetramethyl-piperidin- 4-yloxy)-1H-benzoimidazole  62

2-[3-(4-butoxy-phenoxy)-phenyl]- 1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  63

[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]- diethyl-amine  64

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3-(3-methyl-butyl)-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine  65

[3-(2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3-hexyl-3H-benzimidazol-5-yloxy)-propyl]- diethyl-amine  66

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-diethylamino-ethoxy)- benzimidazol-1-yl]-propyl}- dimethyl-amine  67

1-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-6-(2-piperazin-1- ylethoxy)-1H-benzoimidazole  68

[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]- diethyl-amine  69

{3-[2-(4-benzyloxy-3,5-dimethyl- phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine  70

{3-[3-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine  71

1-butyl-6-[2-(4-methyl-piperazin- 1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole  72

1-butyl-6-[2-(4-isopropyl- piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazole  73

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(3-piperazin-1-yl-propoxy)-1H- benzoimidazole  74

(3-{3-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)- diethyl-amine  75

1-butyl-2-[3-(3,4-dimethoxy- phenoxy)-phenyl]-6-(2-piperidin-4-yloxy)-1H-benzoimidazole  76

1-butyl-2-[3-(4-chloro- benzyloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole  77

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  78

(3-{2-[2-(4-benzyloxy-phenyl)- ethyl]-3-butyl-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine  79

(3-{3-butyl-2-[2-(4-phenethyloxy- phenyl)-ethyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine  80

{3-[3-butyl-2-(2-{4-[2-(4-fluoro- phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine  81

[3-(3-butyl-2-{2-[4-(4-chloro- benzyloxy)-phenyl]-ethyl}-3H-benzimidazol-5-yloxy)-propyl]- diethyl-amine  82

(3-{3-butyl-2-[4-(4-fluoro- benzyloxy)-phenyl]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine  83

{3-[2-(3-benzyloxy-phenyl)-3- butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine  84

[3-(3-butyl-2-{4-chloro-3-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine  85

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole  86

1-butyl-2-[4-(4-isopropyl- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  87

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-[3-(4-methyl-piperazin-1-yl)-propoxy]- 1H-benzoimidazole  88

1-butyl-6-[2-(4-butyl-piperazin-1- yl)-ethoxy]-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H- benzoimidazole  89

1-butyl-2-[3-(3,4-dimethoxy- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  90

1-butyl-2-[4-(4-tert-butyl-benzyl)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  91

N-{4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-2-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-2,2-dimethyl- propioinamide  92

(3-{3-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine  93

1-butyl-2-[4-(naphthalen-2- yloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole  94

1-butyl-2-[3-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole  95

[3-(3-butyl-2-{4-[2-(4-methoxy- phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]- diethyl-amine  96

4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-2-[2-(4-chloro-phenyl)- ethoxy]-phenylamine  97

1-{4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-2-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3-isopropyl-urea  98

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-dimethylamino-ethoxy)- benzimidazol-1-yl]-propyl}- dimethyl-amine  99

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H- benzimidazole 100

1-butyl-6-(4-cyclopentyl- phenoxy)-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]- 1H-benzoimidazole 101

{3-[2-(4-benzyloxy-phenyl)-3- cyclopentylmethyl-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 102

1-butyl-6-(4-butyl-phenoxy)-2- {3,5-dimethyl-4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}- 1H-benzoimidazole 103

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(3-pyrrolidin-1-yl-propoxy)-1H- benzoimidazole 104

{3-[2-(4-benzyloxy-phenyl)-3- isobutyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 105

[3-(3-butyl-2-{3-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]- diethyl-amine 106

1-butyl-6-(1-butyl-piperidin-4- yloxy)-2-[3-(3,5-dichloro-phenoxy)-phenyl]-1H- benzoimidazole 107

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(1-ethyl-piperidin-4-yloxy)-1H- benzoimidazole 108

1-butyl-6-(4-fluoro-3- trifluoromethyl-phenoxy)-2-[4-(4-methyl-piperazin-1-ylmethyl)- phenyl]-1H-benzoimidazole 109

diethyl-{3-[3-isobutyl-2-(2-{4-[2- (4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol- 5-yloxy]-propyl}-amine 110

{3-[2-(2-{4-[2-(4-chlorophenyl)- ethoxy]-phenyl}-ethyl)-3-isobutyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 111

1-butyl-6-(2-piperazin-1-yl- ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzimidazole 112

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 113

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]- 1H-benzimidazole 114

{3-[2-(4-benzyloxy-phenyl)-3- cyclopentyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 115

1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-5-(4-methyl-piperazin-1-ylmethyl)-1H- benzoimidazole 116

[2-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-ethyl]- dimethyl-amine 117

[2-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-ethyl]- diisopropyl-amine 118

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H- benzimidazole 119

(3-{1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)- diethyl-amine 120

2-(3-butoxy-phenyl)-1-butyl-6- (2-piperazin-1-yl-ethoxy)-1H-benzimidazole 121

1-butyl-2-[3-(4-methanesulfonyl- benzyloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 122

4′{3-[1-butyl-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazol-2-yl]-phenoxy}-biphenyl-4-carbonitrile 123

{3-[2-(4-benzyloxy-phenyl)-3- butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 124

1-Butyl-2-[4-(3-chloro-phenoxy)- phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 125

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-[2-(4-isopropyl-piperazin-1-yl)- ethoxy]-1H-benzoimidazole 126

{3-[2-(3-benzyloxy-4-methoxy- phenyl)-3-butyl-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 127

(3-{3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)- diethyl-amine 128

{3-[3-butyl-2-(3-phenoxy- phenyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 129

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-1H- benzimidazole 130

1-butyl-2-[4-(2,3-di-methoxy- phenoxy)-phenyl]-6-(2-piperazin-1-ylethoxy)-1H-benzoimidazole 131

[3-(3-butyl-2-{2-[4-(4-chloro- benzyloxy)-phenyl]-ethyl}-3H-benzimidazol-5-yloxy)-propyl]- diethyl-amine 132

(3-{3-butyl-2-[3-(4-chloro- phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)- diethyl-amine 133

{3-[2-(4-benzyloxy-phenyl)-3- isopropyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 134

(2-{3-butyl-2-[3-(3- trifluoromethyl-phenoxy)-phenyl]-3H-benzoimidazol-5- yloxy}-ethyl)-diisopropyl-amine 135

1-butyl-6-[2-(4-ethyl-piperazin- 1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 136

(3-[3-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 137

(3-{2-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-ethyl)- cyclohexyl-methyl-amine 138

1-butyl-6-[2-(4-propyl-piperazin- 1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 139

1-butyl-6-(4-butyl-phenoxy)-2-[4- (4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-benzoimidazole 140

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-morpholin-4-yl-ethoxy)-1H- benzimidazole 141

4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-2-phenethyloxy-phenylamine 142

{2-[2-(4-benzyloxy-phenyl)-3- phenethyl-3H-benzimidazol-5-yloxy]-ethyl}-diethyl-amine 143

{3-[3-butyl-2-(4-phenoxy- phenyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 144

3-[4-(2-{3-butyl-2-[3-(3,4- dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-ethyl)- piperazin-1-yl]-propan-1-ol 145

1-butyl-6-(2-pyrrolidin-1-yl- ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzimidazole 146

(2-[2-[4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-diethylamino-ethoxy)- benzimidazol-1-yl]-ethyl}- dimethyl-amine 147

1-butyl-6-(2-morpholin-4-yl- ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzimidazole 148

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(1-methyl-piperidin-4-yloxy)-1H- benzoimidazole 149

N′-[3-butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yl]-N,N- diethyl-propane-1,3-diamine 150

1-butyl-2-[3-(2,4-dichloro- phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 151

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-morpholin-4-yl-ethoxy)-1H- benzimidazole 152

1-butyl-6-(2-piperazin-1-yl- ethoxy)-2-[4-(4-trifluoromethyl-phenoxy)-phenyl]-1H- benzoimidazole 153

2-[4-(biphenyl-4-yloxy)-phenyl]- 1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 154

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-morpholin-4-yl-ethoxy)-1H- benzimidazole 155

1-butyl-2-[3-(3,4-dimethoxy- phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 156

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-5-(1H-imidazol-4-ylmethoxy)-1H- benzoimidazole 157

{3-[2-(2-benzyloxy-phenyl)-3- butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 158

{3-[1-Butyl-6-(3-diethylamino- propoxy)-2-piperidin-4-yl-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 159

(2-{2-[2-(4-Benzyloxy-phenyl)- ethyl]-3-phenethyl-3H-benzoimidazol-5-yloxy}-ethyl)- diethyl-amine 160

[3-(3-Butyl-2-{3-[4-(4-fluoro- benzyloxy)-phenyl]-propyl}-3H-benzoimidazol-5-yloxy)-propyl]- diethyl-amine 161

[3-(4-Benzyloxy-phenyl)-propyl]- [1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-2- yl]-amine 162

{3-[3-Butyl-2-(3-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-propyl)-3H-benzoimidazol-5-yloxy]- propyl}-diethyl-amine 163

1-Butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-imidazol-1-yl-ethoxy)-1H-benzoimidazole 164

1-[4-(2-{3-Butyl-2-[3-(3- trifluoromethyl-phenoxy)-phenyl]-3H-benzoimidazol-5- yloxy}-ethyl)-piperazin-1-yl]- ethanone 165

N-[3-Butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzoimidazol-5-yl]-N-(3- diethylamino-propyl)-N′,N′-diethyl-propane-1,3-diamine 166

{3-[1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(3-diethylamino-propoxy)-1H- benzimidazol-4-yl]-propyl}- diethyl-amine 167

{3-[1-Butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine168

{3-[2-(2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-ethyl)-6-(3-diethylamino-propoxy)-3H- benzimidazol-4-yloxy]-propyl}- diethyl-amine169

{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy)-propyl}-diethyl-amine 170

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 171

{3-[2-[3-(3,5-Dichloro-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 172

1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 173

{3-[2-[3-(3,4-Dichloro-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 174

(3-{6-(3-diethylamino-propoxy)- 2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazol-4- yloxy)-propyl)-diethyl-amine 175

{3-[1-Butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine176

{3-[2-[3-(4-Chloro-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 177

{3-[1-Butyl-2-[3-(4-chloro- phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine178

{3-[1-Butyl-6-(3-diethylamino- propoxy)-2-(3-p-tolyloxy-phenyl)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 179

{3-[1-Butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine180

1-Butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 181

{3-[3-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-7-(2-pyrrolidin-1-yl-ethoxy)-3H- benzoimidazol-5-yloxy]-propyl}-diethyl-amine 182

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(3-fluoro-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 183

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(3-diethylamino-propoxy)-1- isopropyl-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 184

{3-[1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 185

2-{4-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-benzimidazol-2-yl-phenoxy}- benzoic acid methyl ester 186

{3-[2-[4-(biphenyl-4-yloxy)- phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine187

{3-[2-[4-(3,5-Bis-trifluoromethyl- phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine188

{3-[1-butyl-2-[4-(4-chloro- benzylsulfanyl)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}- diethyl-amine189

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(3-diethylamino-propoxy)-3H- benzimidazol-4-yloxy]-propyl}- diethyl-amine190

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 191

[3-(1-butyl-6-(3-diethylamino- propoxy)-2-{4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine192

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-{4-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 193

{3-[2-[3-(4-tert-Butyl-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 194

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-5-trifluoromethyl-phenoxy)-2- trifluoromethyl-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 195

{3-[1-Butyl-2-[4-chloro-2-(4- chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 196

2-[3-(4-Chloro-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 197

1-Butyl-2-[3-(4-chloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 198

{3-[3-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-7-(2-pyrrolidin-1-yl- ethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 199

{2-[1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-diisopropylamino-ethoxy)-1H- benzimidazol-4-yloxy]-ethyl}- diethyl-amine200

{3-[2-[4-(3,5-Bis-trifluoromethyl- phenoxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine201

{3-[2-[4-(3,5-Bis-trifluoromethyl- phenoxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine202

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 203

1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 204

2-{4-[2-(4-Chloro-phenyl)- ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 205

1-Butyl-2-[4-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 206

1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 207

{3-[1-Butyl-2-[4-(3-chloro- phenoxy)-phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]- propyl)-diethyl-amine208

2-[5,7-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]- phenol 209

2-[3-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzimidazole 210

(3-{6-(3-Diethylamino-propoxy)- 2-[2-(1,1-difluoro-ethyl)-4-(4-fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy)-propyl)- diethyl-amine 211

{3-[1-Butyl-2-[4-(4-tert-butyl- phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine212

2-[4-(4-tert-Butyl-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 213

{3-[1-Butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 214

[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-diethylaminomethyl-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine 215

(3-{6-(3-Diethylamino-propoxy)- 2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine 216

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-phenyl]- 1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 217

{3-[6-(3-Diethylamino-propoxy)- 2-(3-p-tolyloxy-phenyl)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 218

4-{3-[1-Butyl-4,6-bis-(3- diethylamino-propoxy)-1H-benzoimidazol-2-yl]-phenoxy}- benzonitrile 219

[3-(3-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-7-pyrrolidin-1-yl-3H- benzoimidazol-5-yloxy)-propyl]- diethyl-amine 220

{3-[1-butyl-2-[4-(4-chloro- phenylmethanesulfinyl)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-diethyl-amine 221

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(naphthalen-2-yloxy)-phenyl]-1H- benzoimidazole-4-yloxy}- propyl)-diethyl-amine 222

(3-{6-(3-diethylamino-propoxy)- 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazol-4- yloxy)-propyl)-diethyl-amine 223

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[3-(4-methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 224

2-[3-(3,4-Dichloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 225

{3-[2-[4-(4-tert-Butyl-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 226

{3-[3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-7-[2-(tetrahydro-furan-2-yl)-ethoxy]- 3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 227

1-Butyl-2-[4-(3-chloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 228

[3-(7-Butoxy-3-butyl-2-{4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-3H-benzoimidazol-5-yloxy)- propyl]-diethyl-amine 229

4-{3-[4,6-Bis-(3-diethylamino- propoxy)-1H-benzoimidazol-2-yl]-phenoxy}-benzonitrile 230

2-[3-(3,5-Dichloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 231

{3-[1-butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-6-(3-diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-diethyl-amine 232

{3-[1-butyl-6-(3-diethylamino- propoxy)-2-(3-phenoxy-phenyl)-1H-benzimidazol-4-yloxy]- propyl}-diethyl-amine 233

{3-[1-Butyl-2-[2-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 234

2-[4-(4-Chloro-3-trifluoromethyl- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 235

{3-[1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 236

[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-methyl-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 237

{3-[1-butyl-6-(3-diethylamino- propoxy)-2-(4-phenoxy-phenyl)-1H-benzimidazol-4-yloxy]- propyl}-diethyl-amine 238

5-[4,6-bis-(3-diethylamino- propoxy)-1H-benzoimidazlo-2-yl]-2-[2-(4-chloro-phenyl)- ethoxy]-phenol 239

[3-(6-Butoxy-1-butyl-2-{4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-1H-benzoimidazol-4-yloxy)- propyl]-diethyl-amine 240

{3-[2-[4-Chloro-2-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 241

1-butyl-4-(4-chloro-benzyloxy)-2- {4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazole 242

4-{4-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-benzimidazol-2-yl]-phenoxy}- benzonitrile 243

[3-(1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-fluoro-1H-benzoimidazol-4- yloxy)-propyl]-diethyl-amine 244

(3-{6-(3-diethylamino-propoxy)- 2-[3-(4-methoxy-phenoxy)-phenyl]-1H-benzimidazol-4- yloxy}-propyl)-diethyl-amine 245

(3-{6-(3-diethylamino-propoxy)- 2-[4-(4-methoxy-phenoxy)-phenyl]-1H-benzimidazol-4- yloxy}-propyl)-diethyl-amine 246

{3-[1-butyl-2-[4-(4-chloro-3- fluoro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzimidazol-4-yl]-propyl}- diethyl-amine 247

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(quinolin-8-yloxy)-phenyl]-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 248

{3-[2-[2-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 249

2-[{2-[1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-morpholin-4-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-ethyl}-(2-chloro-ethyl)-amino]-ethanol 250

(3-{6-(3-Diethylamino-propoxy)- 2-[3-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine 251

[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-7-isopropoxy-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 252

[3-(1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-cyclopentylmethoxy-1H- benzoimidazol-4-yloxy)-propyl]- diethyl-amine 253

1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-4,6-bis-(2-morpholin-4-yl-ethoxy)-1H- benzoimidazole 254

{3-[2-[4-[2-(4-Chloro-phenyl)- ethoxy]-3-(3-diethylamino-propoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 255

{3-[2-[1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)- phenoxy]-propyl}-diethyl-amine 256

(3-{2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 257

(3-{1-butyl-6-(4-tert-butyl- phenoxy)-2-[4-(3-diethylamino-propoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine 258

2-{2,4-bis-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-tert-butyl-phenoxy)- 1H-benzoimidazole 259

2-[2,4-bis-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1-butyl-6-(4-butyl-phenoxy)-1H- benzoimidazole 260

1-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolodin-1-yl-ethoxy)-phenyl]-6-(2-pyrrolodin- 1-yl-ethoxy)-1H-benzoimidazole 261

{3-[2-{1-butyl-6-[2-(4-chloro- phenyl)-ethoxy]-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 262

2-{2,4-bis-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-butyl-phenoxy)-1H- benzoimidazole 263

{3-[2-[1-butyl-5-(4-tert-butyl- phenoxy)-1H-benzimidazol-1-yl]-5-(3-diethylamino-propoxy)- phenoxy]-propyl}-diethyl-amine 264

1-Butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 265

2-[2,4-bis-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1-butyl-6-(4-cyclopentyl-phenoxy)-1H- benzoimidazole 266

2-{2,4-bis-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzoimidazole 267

{3-[2-[1-butyl-6-(4-iospropyl- phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)- phenoxy]-propyl}-diethyl-amine 268

(2-{1-butyl-6-(2-dimethylamino- ethylsulfanyl)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-ylsulfanyl}- ethyl)-dimethyl-amine 269

2-[2,4-bis-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1-butyl-6-(4-tert-butyl-phenoxy)-1H- benzimidazole 270

{3-[2-[1-butyl-6-(4-butyl- phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)- phenoxy]-propyl}-diethyl-amine 271

{3-[2-[1-butyl-6-(4-fluoro-3- trifluoromethyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 272

2-[2,4-bis-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1-butyl-6-(4-isopropyl-phenoxy)-1H- benzoimidazole 273

1-Butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 274

(3-{3-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 275

{3-[2-[1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)- phenoxy]-propyl}-diethyl-amine 276

{3-[2-[1-butyl-4-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)- phenoxy]-propyl}-diethyl-amine 277

2-{2,4-bis-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-isopropyl-phenoxy)- 1H-benzoimidazole 278

(3-{5-[2-(4-chloro-phenyl)- ethoxy]-2-[6-(3-diethylamino-propoxy)-1-isopropyl-1H- benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine 279

1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 280

1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-4,6-bis-(1-methyl-piperidin-4-yloxy)-1H- benzimidazole 281

{3-[2-[6-(4-tert-butyl-phenoxy)- 1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 282

1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolidin-2-ylmethoxy)- 1H-benzoimidazole 283

(3-{3-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-diethylamino-ethoxy)-phenyl]- 3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 284

(3-{2-[1-Butyl-6-(2-imidazol-1- yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)- ethoxy]-phenoxy}-propyl)- diethyl-amine 285

(3-{2-[1-Butyl-6-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)- ethoxy]-phenoxy}-propyl)- diethyl-amine 286

{3-[2-(3,5-bis-benzyloxy-phenyl)- 3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 287

4,6-bis-(2-azepan-1-yl-ethoxy)-1- butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-1H-benzoimidazole 288

1-butyl-2-[3-(4-butyl-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 289

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolidin-2-ylmethoxy)- 1H-benzoimidazole 290

(2-{1-butyl-6-(2-dimethylamino- ethylsulfanyl)-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazole-4-ylsufanyl}-ethyl)-dimethyl-amine 291

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-isopropyl-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 292

4,6-bis-(2-azepan-1-yl-ethoxy)-1- butyl-2-[3-(3,5-dichlorophenoxy)-phenyl]-1H-benzoimidazole 293

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-[2-(cyclohexyl-methyl-amino)- ethoxy]-1H-benzoimidazole 294

{3-[1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-imidazol-1-yl-ethoxy)-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 295

[3-(2-{3,4-bis-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3-butyl-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 296

1-butyl-4,6-bis-(1-methyl- piperidin-4-yloxy)-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazole 297

4,6-bis-(2-azepan-1-yl-ethoxy)-1- butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzoimidazole 298

1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidin-2-ylmethoxy)- 1H-benzoimidazole 299

[3-(2-{2-benzyloxy-4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-3-butyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 300

{3-[2-[1-Butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl- phenoxy)-phenoxy]-propyl}-diethyl-amine 301

{3-[2-[1-Butyl-6-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl- phenoxy)-phenoxy]-propyl}-diethyl-amine 302

1-butyl-2-[3-(3,4-dimethoxy- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 303

(2-{1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-dimethylamino-ethylsulfanyl)- 1H-benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine 304

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidin-3-yloxy)-1H- benzoimidazole 305

{3-[2-[3-(3,4-bis-benzyloxy- phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 306

(3-{5-[2-(4-chloro-phenyl)- ethoxy]-2-[6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]- phenoxy}-propyl)-diethyl-amine 307

1-butyl-2-[4-(2-diethylamino- ethoxy)-phenyl]-4,6-bis-[2-(methyl-phenyl-amino)-ethoxy]- 1H-benzimidazole 308

{3-[3-butyl-2-{4-[2-(4- chlorophenyl)-ethoxy]-phenyl}-7-(pyridin-3-yloxy)-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine 309

{2-[1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(2-diisopropylamino-ethoxy)-1H- benzimidazol-4-yloxy]-ethyl}- diethyl-amine310

{3-[3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-7-(pyridin-3-ylmethoxy)-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine311

2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4-chloro-phenyl)- ethoxy]-phenol 312

{3-[3-butyl-2-[2-(4-chloro- phenylsulfanyl)-phenyl]-7-(3-diethylamino-propoxy)-3H- benzimidazol-4-yloxy}-propyl)- diethyl-amine313

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-2-methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)-diethyl-amine 314

[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-2-isopropoxy-phenyl}-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 315

{2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4-chloro-phenyl)- ethoxy]-phenoxy}-acetic acid methyl ester316

(3-{2-[1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 317

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(2-isopropoxy-phenoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine 318

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(2,3-dimethoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 319

(3-{3-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-propyl)- diethyl-amine320

(2-{1-butyl-6-fluoro-2-[3-(3- trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole-4- ylsufanyl}-ethyl)-dimethyl-amine 321

Methanesulfonic acid 5-[2-(4- chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H- benzoimidazol-2-yl]-phenyl ester 322

5-[2-(4-Chloro-phenyl)-ethoxy]- 2-[6-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-phenol 323

{3-[1-butyl-6-(3-diethylamino- propoxy)-2-(4-pyrrolidin-1-yl-phenyl)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 324

1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-(1-methyl-piperidin-4-yloxy)-1H- benzimidazole 325

1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-4,6-bis-(2-imidazol-1-yl-ethoxy)-1H- benzoimidazole 326

[2-(1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-fluoro-1H-benzoimidazol-4- ylsulfanyl)-ethyl]-dimethyl-amine 327

{3-[1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-(pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 328

1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 329

1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 330

(3-{2-[1-butyl-6-(3-diethylamino- propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]- 5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 331

(3-{2-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 332

(3-{2-[1-Butyl-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 333

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 334

{3-[1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 335

{3-[2-[1-Butyl-6-(3-diethylamino- propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]- 5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}- diethyl-amine 336

(3-[2-[1-Butyl-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 337

{3-[3-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-(2- pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 338

(3-{2-[1-Butyl-4-(3-diethylamino- propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]- 5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 339

{3-[1-butyl-2-[4-(3,4-dichloro- phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 340

{3-[2-[2,4-bis-(3-diethylamino- propoxy)-phenyl]-1-butyl-6-(4-tert-butyl-phenoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine341

{3-[1-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yl]-phenyl}- diethyl-amine 342

{3-[2-[4-[2-(4-Chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 343

1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 344

{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 345

(3-{6-(3-Diethylamino-propoxy)- 2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 346

{3-[2-[1-Butyl-4-(3-diethylamino- propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]- 5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}- diethyl-amine 347

{3-[3-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzoimidazol-5-yloxy]-propyl}- diethyl-amine 348

{3-[1-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(2- pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 349

{3-[2-[1-butyl-4,6-bis-(2- pyrrolodin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine 350

{3-[1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-3-diethylaminomethyl-phenyl}-6- (3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 351

{3-[2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-yl]-propyl}-diethyl-amine 352

3-(7-Butoxy-3-butyl-2-{4-[2-(4- chloro-phenyl)-ethoxy]-2-cyclopentylmethoxy-phenyl}-3H- benzoimidazol-5-yloxy)-propan- 1-ol 353

3-(7-Butoxy-2-{4-[2-(4-chloro- phenyl)-ethoxy]-2-cyclopentylmethoxy-phenyl}-3H- benzoimidazol-5-yloxy)-propan- 1-ol 354

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2- (pyridin-2-ylmethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 355

{3-[2-[1-Butyl-4,6-bis-(3- diethylamino-propoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 356

2-(3,5-bis-benzyloxy-phenyl)-1- butyl-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzimidazole 357

{3-[2-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine 358

1-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrol-1-yl-ethoxy)-phenyl]-4,6-bis-(2-pyrrolodin-1- yl-ethoxy)-1H-benzoimidazole 359

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-propoxy)-phenyl}-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 360

{3-[1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(pyridin-3-ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 361

(3-{3-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl]- 7-isopropoxy-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 362

{3-[1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 363

{3-[2-[4-[2-(4-Chloro-phenyl)- ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 364

1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 365 cor- rect

2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,7-bis-(2- pyrrolidin-1-yl-ethoxy)-1H- benzimidazole366

{3-[1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-2-methoxy-phenyl}-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 367

{3-[2-{4-[2-(4-Chloro-phenyl)- ethoxy]-2-methoxy-phenyl}-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 368

(3-{1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl]- 6-isopropoxy-1H-benzoimidazol-4-yloxy)-propyl)-diethyl-amine 369

{3-[1-Butyl-2-[4-(4-chloro-3- methyl-phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 370

1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-4,6- bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 371

(2-{1-butyl-6-(2-dimethylamino- ethoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}- ethyl)-dimethyl-amine 372

2-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenol 373

1-Butyl-2-[4-(4-chloro-3-methyl- phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 374

2-[4-(4-Chloro-3-trifluoromethyl- phenoxy)-2-cyclopentylmethoxy-phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 375

2-[4-(4-Fluoro-3-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole376

{3-[2-(3,5-bis-benzyloxy-phenyl)- 1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 377

(3-{1-butyl-6-(3-dimethylamino- propoxy)-2-[4-(3-fluoro-phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}- propyl)-diethyl-amine 378

{3-[2-{1-butyl-4-(4-chloro- benzyloxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 379

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-propoxy)-phenyl]-6-(3- diethylamino-propoxy)-3H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 380

{3-[2-[4-(3,4-dichloro-phenoxy)- 2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 381

{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-6- (3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 382

{3-[2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-6- (3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 383

(3-{1-butyl-6-(4-tert-butyl- phenoxy)-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3- diethylamino-propoxy)-phenyl]-1H-benzimidazol-4-yloxy}- propyl)-diethyl-amine 384

2-{2,4-bis-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-1-butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 385

(2-{1-butyl-6-(2-dimethylamino- ethoxy)-2-[4-(3-fluoro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-benzoimidazole-4-yloxy)-ethyl)-dimethyl-amine 386

{3-[2-[4-(3,5-bis-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 387

{3-[1-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 388

(3-{2-(1-Butyl-4,6-diisopropoxy- 1H-benzoimidazol-2-yl)-5-[2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 389

{3-[1-butyl-2-{3-[2-(4-chloro- phenyl)-ethoxy]-4-diethylaminomethyl-phenyl}-6- (3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 390

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-fluoro-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 391

(2-{1-butyl-6-fluoro-2-[4-(4- fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-benzoimidazol-4-ylsulfanyl}- ethyl)-dimethyl-amine 392

{3-[1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-3-(3-diethylamino-propoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 393

(4-benzyloxy-benzyl)-[1-butyl-6- (3-diethylamino-propoxy)-1H-benzimidazol-2-ylmethyl]-hexyl- amine 394

(4-benzyloxy-benzyl)-[1-butyl-6- (3-diethylamino-propoxy)-1H-benzimidazol-2-ylmethyl]- isobutyl-amine 395

[3-(2-{[(4-benzyloxy-benzyl)- cyclopentylmethyl-amino]-methyl}-3-butyl-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine 396

N-(4-benzyloxy-benzyl)-N-[1- butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2- ylmethyl]-benzamide 397

(3-{3-butyl-2-[(dibenzylamino)- methyl]-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 398

(3-{2-[(4-benzyloxy- benzylamino)-methyl]-3-butyl-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 399

N-(4-benzyloxy-benzyl)-N-[1- butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2- ylmethyl]-methanesulfonamide 400

N-(4-benzyloxy-benzyl)-N-[1- butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2- ylmethyl]-acetamide 401

{3-[3-butyl-2-({4-[2-(4-chloro- phenyl)-ethoxy]-benzylamino}-methyl)-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 402

[3-(2-{[Bis-(4-benzyloxy-benzyl)- amino]-methyl}-3-butyl-3H-benzoimidazol-5-yloxy)-propyl]- diethyl-amine 403

[3-(2-{[Benzyl-(4-benzyloxy- benzyl)-amino]-methyl}-3-butyl-3H-benzoimidazol-5-yloxy)- propyl]-diethyl-amine 404

{3-[4-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 405

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 406

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 407

1-[4-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-butyl]-piperazine 408

4-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-1-methyl-piperidine 409

1-[5-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-pentyl]-piperazine 410

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine 411

{3-[3-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine 412

[3-(4-{1-[4-(4-tert-butyl- phenoxy)-phenyl]-1H-imidazol-4-yl)-phenoxy)-propyl]-diethyl- amine 413

[3-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 414

diethyl-[3-(4-{1-[4-(4- trifluoromethoxy-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-amine 415

[3-(4-{2-butyl-1-[4-(3,4-dichloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 416

[3-(4-{2-cyclobutyl-1-[4-(4- fluoro-3-trifluoromethyl-phenoxy)-phenyl}-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 417

[3-(4-{2-cyclopentyl-1-[4-(4- fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 418

[3-(4-{2-cyclohexyl-1-[4-(4- fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 419

diethyl-[3-(4-{1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-2-isobutyl-1H-imidazol- 4-yl}-phenoxy)-propyl]-amine 420

[3-(4-{2-but-3-enyl-1-[4-(4- fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 421

[3-(4-{2-tert-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 422

diethyl-[3-(4-{2-(4-fluoro- phenyl)-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl)-phenoxy)-propyl]-amine 423

[3-(4-{1-[4-(3,5-bis- trifluoromethyl-phenoxy)-phenyl]-2-butyl-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl- amine 424

(3-{4-[1-(4-benzyloxy-phenyl)-2- butyl-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine 425

{3-[4-(2-tert-butyl-4-{4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 426

[3-(4-{2-butyl-1-[4-(3-fluoro-4- trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 427

diethyl-[3-(4-{4-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)- propyl]-amine 428

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(4-fluoro-phenyl)-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 429

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-cyclopropyl-imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 430

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-cyclopentyl-imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 431

[3-(4-{4-[4-(biphenyl-4-yloxy)- phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 432

diethyl-[3-(4-{4-[4-(3- trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)- propyl]-amine 433

[3-(4-{4-[4-(3,4-dichloro- phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 434

[3-(4-{2-butyl-1-[4-(4-methoxy- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 435

1-[2-(4-{2-butyl-1-[4-(3-fluoro-4- trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-ethyl]-piperazine 436

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-dimethyl- amine 437

4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-1-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]- phenyl}-1H-imidazole 438

1-{2-[4-(4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}- piperazine 439

[3-(4-{2-(3-cyclohexyl-propyl)- 1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 440

diethyl-(3-{4-[1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-2-(3-phenoxy-propyl)- 1H-imidazol-4-yl]-phenoxy}- propyl)-amine441

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-methyl-imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 442

3-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-1-ethyl-piperidine 443

diethyl-[3-(4-{1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-2-methyl-1H-imidazol- 4-yl}-phenoxy)-propyl]-amine 444

(3-{4-[4-(4-benzyloxy-phenyl)-2- butyl-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine 445

[3-(4-{2-butyl-1-[4-(2,5-difluoro- benzyloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 446

3-(S)-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxymethyl)-1-ethyl- piperidine 447

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(2,4,4-trimethyl-pentyl)-imidazol-1-yl]- phenoxy}-propyl)-diethyl-amine 448

3-(R)-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxymethyl)-1-ethyl- piperidine 449

[3-(4-{2-butyl-1-[4-(3-tert-butyl- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 450

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-methoxymethyl-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 451

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(1-ethyl-propyl)-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 452

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(3-phenoxy-propyl)-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 453

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(1-propyl-butyl)-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 454

{3-[4-(2-(4-chloro- phenoxymethyl)-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}- imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine 455

{3-[4-(2-benzyloxymethyl-4-{4- [2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 456

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-5-methyl-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 457

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-5-propyl-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 458

{3-[4-(5-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 459

{4-{4-{2-(4-chloro-phenyl)- ethoxy]-phenyl}-1-[4-(3-diethylamino-propoxy)-phenyl]- 1H-imidazol-2-yl}-MeOH 460

diethyl-[3-(4-{2-isobutyl-4-[4-(4- phenoxy-benzyloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]- amine 461

[3-(4-{4-[4-(4-benzyloxy- benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 462

[3-(4-{4-[4-(2- benzenesulfonylmethyl- benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 463

diethyl-[3-(4-{2-isobutyl-4-[4- (3,4,5-trimethoxy-benzyloxy)-phenyl]-imidazol-1-yl}-phenoxy)- propyl]-amine 464

[3-(4-{1-[4-(4-chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 465

[3-(4-{1-[4-(4-chloro-phenoxy)- phenyl]-2-(2-cyclopentyl-ethyl)-1H-imidazol-4-yl}-phenoxy)- propyl]-diethyl-amine 466

[3-(4-{1-[4-(4-chloro-phenoxy)- phenyl]-2-phenethyl-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 467

[3-(4-{2-(4-tert-butyl- phenoxymethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol- 4-yl]-phenoxy)-propyl]-diethyl- amine 468

[3-(4-{2-butyl-1-[4-(2,4-dichloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 469

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-5-methyl-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 470

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-5-propyl-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 471

[3-(4-{2,5-dibutyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 472

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-5-ethyl-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 473

2-butyl-1-[4-(4-chloro-phenoxy)- phenyl]-4-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-imidazole 474

1-[2-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-piperidine 475

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-2,2-dimethyl- propyl]-dimethyl-amine 476

[2-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-diisopropyl- amine 477

[3-(4-{4-[4-(adamantan-1- ylmethoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 478

{3-[4-(4-{4-[3-(2,6-dichloro- phenyl)-4-methyl-isoxazol-5-ylmethyloxy]-phenyl}-2-isobutyl- imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine 479

[3-(4-{4-[4-(4-bromo-benzyloxy)- phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl- amine 480

[3-(4-{2-butyl-1-[4-(6-methoxy- naphthalen-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 481

[3-(4-{2-butyl-1-[4-(naphthalen- 2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 482

[3-(4-{2-butyl-1-[4-(4-methoxy- naphthalen-1-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 483

[3-[4-[2-butyl-1-[4-(dibenzofuran- 2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 484

6-(4-{2-butyl-4-[4-(3- diethylamino-propoxy)-phenyl]-imidazol-1-yl]-phenoxy)- naphthalen-2-ol 485

[3-(4-{2-butyl-4-[4-(4-chloro- phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 486

[3-(4-{2-(4-tert-butyl- cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 487

[3-{4-[1-[4-(4-chloro-phenoxy)- phenyl]-2-(trans-4-ethyl-cyclohexyl)-1H-imidazol-4-yl]- phenoxy}-propyl)-diethyl-amine 488

[4-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-phenyl]-(1-ethyl- piperidin-4-ylmethyl)-amine 489

[4-{1-[4-(4-chloro-phenoxy)- phenyl]-4-[4-(3-diethylaminopropoxy)-phenyl]- 1H-imidazol-2-yl}-butyric acid methylester 490

[3-(4-{2-butyl-1-[4-(4-chloro-2- cyclohexyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 491

[3-(4-{1-[4-(biphenyl-4-yloxy)- phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 492

[3-(4-{1-[4-(4-bromo-phenoxy)- phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 493

N-[4-(4-{2-butyl-4-[4-(3- diethylamino-porpoxy)-phenyl]-imidazol-1-yl}-phenoxy)- phenyl]-acetamide 494

(3-{4-[2-butyl-1-(4-p-tolyloxy- phenyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine 495

[3-(4-{2-butyl-1-[4-(4-fluoro- phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl- amine 496

[3-(4-{2-butyl-1-[4-(4-chloro-3- ethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 497

{2-[4-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}- ethyl-amine 498

[3-(4-{5-butyl-4-[4-(3,3-diphenyl- propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-2,2- dimethyl-propyl]-dimethyl-amine 499

[3-(4-{4-[4-(3,3-diphenyl- propoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 500

7-{2-butyl-4-[4-(4-chloro- phenoxy)-naphthalen-1-yl]-imidazol-1-yl}-1,2,3,4-tetrahydro- isoquinoline 501

2-biphenyl-4-yl-N-{4-[2-butyl-1- (1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenyl}- acetamide 502

7-{2-butyl-4-[4-(2,4-dichloro- phenoxy)-phenyl]-1-yl}-1,2,3,4-tetrahydro-isoquinoline 503

7-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-1,2,3,4- tetrahydro-isoquinoline 504

7-[4-(4-benzyloxy-phenyl)-2- butyl-imidazol-1-yl]-1,2,3,4-tetrahydro-isoquinoline hydrochloride hydrochloride 505

9-(2-{4-[2-butyl-1-(1,2,3,4- tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenoxy}-ethyl- 9H-carbazole 506

7-{2-butyl-4-[4-(4-methoxy- phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline 507

7-(2-butyl-4-{4-[2-(4-tert-butyl- phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro- isoquinoline hydrochloride 508

7-{2-butyl-4-[4-(naphthalen-2- ylmethoxy)-phenyl]-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride 509

7-{2-butyl-4-[4-(4- trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4- tetrahydro-isoquinoline hydrochloride510

7-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro- isoquinoline 511

[3-(4-{2-(4-Butyl-cyclohexyl)-1- [4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)- propyl]-diethyl-amine 512

2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine 513

[3-(4-{2-(trans-4-tert-Butyl- cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 514

[3-(4-{2-(cis-4-tert-Butyl- cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]- diethyl-amine 515

[2-(4-{2-Butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-ethyl]-methyl-pyridin- 4-yl-amine516

[2-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl- pyridin-4-yl-amine 517

[2-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl- (3-methyl-pyridin-4-yl)-amine 518

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-ethyl- pyridin-4-yl-amine 519

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-pyridin-4- yl-amine 520

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-bis- pyridin-2-ylmethyl-amine 521

N-[2-(4-{1-[4-(4-Chloro- phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]- guanidine 522

2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-1-(4-pyridin-4- yl-piperazin-1-yl)-ethanone 523

5-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxymethyl)-pyrrolidin- 3-ol 524

3-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-pyridin-4-ylamine 525

(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-pyridin-4-yl-amine 526

2-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxymethyl)-3,5- dimethyl-pyridin-4-ylamine 527

1-[2-(4-{1-[4-(4-Chloro- phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl]-phenoxy)-ethyl]- 4-pyridin-4-yl-piperazine 528

4-(4-{2-Butyl-4-[4-(3- diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)- phenylamine 529

{3-[4-(2-Butyl-4-dibenzofuran- 2-yl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine 530

N-[4-(4-{2-Butyl-4-[4-(3- diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]- benzamide 531

N-[4-(4-{2-Butyl-4-[4-(3- diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]- isonicotinamide 532

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl- pyridin-4-yl-amine 533

N-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-2-dimethylamino- acetamide 534

{3-[4-(4-{4-[3,3-Bis-(4-chloro- phenyl)-allyloxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 535

{3-[4-(4-{4-[3,3-Bis-(4-fluoro- phenyl)-propoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 536

[2-(4-{4-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-ethyl]-methyl- pyridin-4-yl-amine 537

[3-(4-{4-{4-[2-(4-Chloro-phenyl)- ethoxy]-phenyl}-2-[2-(1-methyl-pyridin-3-yl)-ethyl]-imidazol-1- yl}-phenoxy)-propyl]- diethylmethylammonium iodide 538

[3-(4-{2-(N-BOC-piperidine-4- ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 539

[3-(4-{2-(Piperidine-4-ylmethyl)- 1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)- propyl]-diethyl-amine 540

[3-(4-{2-(N-ethyl-piperidine-4- ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine 541

[3-(4-{2-(piperidine-4-ylmethyl)- 4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 542

[3-(4-{2-(N-ethylpiperidine-4- ylmethyl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 543

[3-(4-{2-(N-acetylpiperidine-4- yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 544

[3-(4-{2-(piperidine-4-yl)-4-[4- (4-chloro-phenoxy)-phenyl]-imidazol-1-yl)-phenoxy)-propyl]- diethyl-amine 545

[3-(4-{2-(N-Benzylpiperidine-4- yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 546

[3-(4-{2-(N-(2- Pyridylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 547

[3-(4-{2-(N-(2- Imidazolylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)- phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 548

[3-(4-{2-(N-(4- biphenyl)methylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 549

[3-(4-{2-(N- Cyclohexylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 550

[3-(4-{2-(N-(4- Cyanobenzyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine 551

[3-(4-{2-(N-Ethylpiperidine-4- yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine

DEFINITIONS OF TERMS

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to ten carbon atoms, optionally substitutedwith substituents selected from the group consisting of lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, silyloxy optionally substituted byalkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl,or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multipledegrees of substitution being allowed. Such an “alkyl” group maycontaining one or more O, S, S(O), or S(O)₂ atoms. Examples of “alkyl”as used herein include, but are not limited to, methyl, n-butyl,t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyloptionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen,or lower perfluoroalkyl, multiple degrees of substitution being allowed.Such an “alkylene” group may containing one or more O, S, S(O), or S(O)₂atoms. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, and the like.

As used herein, the term “alkyline” refers to a straight or branchedchain trivalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyloptionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen,or lower perfluoroalkyl, multiple degrees of substitution being allowed.Examples of “alkyline” as used herein include, but are not limited to,methine, 1,1,2-ethyline, and the like.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon doublebond, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyloptionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen,or lower perfluoroalkyl, multiple degrees of substitution being allowed.Such an “alkenyl” group may containing one or more O, S, S(O), or S(O)₂atoms.

As used herein, the term “alkenylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon double bonds, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl,or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such an “alkenylene” group may containingone or more O, S, S(O), or S(O)₂ atoms. Examples of “alkenylene” as usedherein include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon triplebond, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyloptionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen,or lower perfluoroalkyl, multiple degrees of substitution being allowed.Such an “alkynyl” group may containing one or more O, S, S(O), or S(O)₂atoms.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon triple bonds, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl,or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such an “alkynylene” group may containingone or more O, S, S(O), or S(O)₂ atoms. Examples of “alkynylene” as usedherein include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, “cycloalkyl” refers to an alicyclic hydrocarbon groupoptionally possessing one or more degrees of unsaturation, having fromthree to twelve carbon atoms, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degreesof substitution being allowed. “Cycloalkyl” includes by way of examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl, and the like.

As used herein, the term “cycloalkylene” refers to an non-aromaticalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms and optionally possessing one or more degrees ofunsaturation, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered heterocyclic ring optionallypossessing one or more degrees of unsaturation, containing one or moreheteroatomic substitutions selected from S, SO, SO₂, O, or N, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Such a ring may be optionally fused to one or more of another“heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic”include, but are not limited to, tetrahydrofuran, 1,4-dioxane,1,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and thelike.

As used herein, the term “heterocyclyl containing at least one basicnitrogen atom” refers to a “heterocyclic” “heterocyclyl group as definedabove, wherein said heterocyclyl group contains at least one nitrogenatom flanked by hydrogen, alkyl, alkylene, or alkylyne groups, whereinsaid alkyl and/or alkylene groups are not substituted by oxo. Examplesof “heterocyclyl containing at least one basic nitrogen atom” include,but are not limited to, piperazine-2-yl, pyrrolidine-2-yl, azepine-4-yl,

and the like.

As used herein, the term “heterocyclylene” refers to a three totwelve-membered heterocyclic ring diradical optionally having one ormore degrees of unsaturation containing one or more heteroatoms selectedfrom S, SO, SO₂, O, or N, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degreesof substitution being allowed. Such a ring may be optionally fused toone or more benzene rings or to one or more of another “heterocyclic”rings or cycloalkyl rings. Examples of “heterocyclylene” include, butare not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,morpholine-2,4-diyl, piperazine-1,4-diyl, and the like.

As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy optionally substituted by acyl, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, oraryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of aryl include, but are notlimited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the like.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted byalkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl,or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multipledegrees of substitution being allowed. Examples of “arylene” include,but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and thelike.

As used herein, the term “heteroaryl” refers to a five- toseven-membered aromatic ring, or to a polycyclic heterocyclic aromaticring, containing one or more nitrogen, oxygen, or sulfur heteroatoms,where N-oxides and sulfur monoxides and sulfur dioxides are permissibleheteroaromatic substitutions, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted byalkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl,or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multipledegrees of substitution being allowed. For polycyclic aromatic ringsystems, one or more of the rings may contain one or more heteroatoms.Examples of “heteroaryl” used herein are furan, thiophene, pyrrole,imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole,oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine,pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran,benzothiophene, indole, and indazole, and the like.

As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, oraryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systemdiradicals, one or more of the rings may contain one or moreheteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl,thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

As used herein, the term “fused cycloalkylaryl” refers to one or morecycloalkyl groups fused to an aryl group, the aryl and cycloalkyl groupshaving two atoms in common, and wherein the aryl group is the point ofsubstitution. Examples of “fused cycloalkylaryl” used herein include5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl,

and the like.

As used herein, the term “fused cycloalkylarylene” refers to a fusedcycloalkylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylcycloalkyl” refers to one or morearyl groups fused to a cycloalkyl group, the cycloalkyl and aryl groupshaving two atoms in common, and wherein the cycloalkyl group is thepoint of substitution. Examples of “fused arylcycloalkyl” used hereininclude 1-indanyl, 2-indanyl, 9-fluorenyl,1-(1,2,3,4-tetrahydronaphthyl),

and the like.

As used herein, the term “fused arylcycloalkylene” refers to a fusedarylcycloalkyl, wherein the cycloalkyl group is divalent. Examplesinclude 9,1-fluorenylene,

and the like.

As used herein, the term “fused heterocyclylaryl” refers to one or moreheterocyclyl groups fused to an aryl group, the aryl and heterocyclylgroups having two atoms in common, and wherein the aryl group is thepoint of substitution. Examples of “fused heterocyclylaryl” used hereininclude 3,4-methylenedioxy-1-phenyl,

and the like

As used herein, the term “fused heterocyclylarylene” refers to a fusedheterocyclylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylheterocyclyl” refers to one or morearyl groups fused to a heterocyclyl group, the heterocyclyl and arylgroups having two atoms in common, and wherein the heterocyclyl group isthe point of substitution. Examples of “fused arylheterocyclyl” usedherein include 2-(1,3-benzodioxolyl),

and the like.

As used herein, the term “fused arylheterocyclyl containing at least onebasic nitrogen atom” refers to a “fused arylheterocyclyl” group asdefined above, wherein said heterocyclyl group contains at least onenitrogen atom flanked by hydrogen, alkyl, alkylene, or alkylyne groups,wherein said alkyl and/or alkylene groups are not substituted by oxo.Examples of “fused arylheterocyclyl containing at least one basicnitrogen atom” include, but are not limited to,

and the like.

As used herein, the term “fused arylheterocyclylene” refers to a fusedarylheterocyclyl, wherein the heterocyclyl group is divalent. Examplesinclude

and the like.

As used herein, the term “fused cycloalkylheteroaryl” refers to one ormore cycloalkyl groups fused to a heteroaryl group, the heteroaryl andcycloalkyl groups having two atoms in common, and wherein the heteroarylgroup is the point of substitution. Examples of “fusedcycloalkylheteroaryl” used herein include 5-aza-6-indanyl,

and the like.

As used herein, the term “fused cycloalkylheteroarylene” refers to afused cycloalkylheteroaryl, wherein the heteroaryl group is divalent.Examples include

and the like.

As used herein, the term “fused heteroarylcycloalkyl” refers to one ormore heteroaryl groups fused to a cycloalkyl group, the cycloalkyl andheteroaryl groups having two atoms in common, and wherein the cycloalkylgroup is the point of substitution. Examples of “fusedheteroarylcycloalkyl” used herein include 5-aza-1-indanyl,

and the like.

As used herein, the term “fused heteroarylcycloalkylene” refers to afused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent.Examples include

and the like.

As used herein, the term “fused heterocyclylheteroaryl” refers to one ormore heterocyclyl groups fused to a heteroaryl group, the heteroaryl andheterocyclyl groups having two atoms in common, and wherein theheteroaryl group is the point of substitution. Examples of “fusedheterocyclylheteroaryl” used herein include1,2,3,4-tetrahydro-beta-carbolin-8-yl,

and the like.

As used herein, the term “fused heterocyclylheteroarylene” refers to afused heterocyclylheteroaryl, wherein the heteroaryl group is divalent.Examples include

and the like.

As used herein, the term “fused heteroarylheterocyclyl” refers to one ormore heteroaryl groups fused to a heterocyclyl group, the heterocyclyland heteroaryl groups having two atoms in common, and wherein theheterocyclyl group is the point of substitution. Examples of “fusedheteroarylheterocyclyl” used herein include-5-aza-2,3-dihydrobenzofuran-2-yl,

and the like.

As used herein, the term “fused heteroarylheterocyclyl containing atleast one basic nitrogen atom” refers to a “fusedheteroarylheterocyclyl” group as defined above, wherein saidheterocyclyl group contains at least one nitrogen atom flanked byhydrogen, alkyl, alkylene, or alkylyne groups, wherein said alkyl and/oralkylene groups are not substituted by oxo. Examples of “fusedheteroarylheterocyclyl containing at least one basic nitrogen atom”include, but are not limited to,

and the like.

As used herein, the term “fused heteroarylheterocyclylene” refers to afused heteroarylheterocyclyl, wherein the heterocyclyl group isdivalent. Examples include

and the like.

As used herein, the term “acid isostere” refers to a substituent groupwhich will ionize at physiological pH to bear a net negative charge.Examples of such “acid isosteres” include but are not limited toheteroaryl groups such as but not limited to isoxazol-3-ol-5-yl,1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such acid isosteres include butare not limited to heterocyclyl groups such as but not limited toimidazolidine-2,4-dione-5-yl, imidazolidine-2,4-dione-1-yl,1,3-thiazolidine-2,4-dione-5-yl, or 5-hydroxy-4H-pyran-4-on-2-yl.

As used herein, the term “direct bond”, where part of a structuralvariable specification, refers to the direct joining of the substituentsflanking (preceding and succeeding) the variable taken as a “directbond”. Where two or more consecutive variables are specified each as a“direct bond”, those substituents flanking (preceding and succeeding)those two or more consecutive specified “direct bonds” are directlyjoined.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl.

As used herein, the term “alkenyloxy” refers to the group R_(a)O—, whereR_(a) is alkenyl.

As used herein, the term “alkynyloxy” refers to the group R_(a)O—, whereR₁ is alkynyl.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R₁ is alkyl.

As used herein, the term “alkenylsulfanyl” refers to the group R_(a)S—,where R₁ is alkenyl.

As used herein, the term “alkynylsulfanyl” refers to the group R_(a)S—,where R₁ is alkynyl.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R₁ is alkyl.

As used herein, the term “alkenylsulfenyl” refers to the groupR_(a)S(O)—, where R₁ is alkenyl.

As used herein, the term “alkynylsulfenyl” refers to the groupR_(a)S(O)—, where R_(a) is alkynyl.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R₁ is alkyl.

As used herein, the term “alkenylsulfonyl” refers to the group R₃SO₂—,where R₁ is alkenyl.

As used herein, the term “alkynylsulfonyl” refers to the groupR_(a)SO₂—, where R₁ is alkynyl.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, where R₁is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR₁ is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R₁ is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R₁ is alkyl.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R₁ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R₁ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, or heterocyclyl.

As used herein, the term “aryloxycarbonyl” refers to the groupR_(a)OC(O)—, where R₁ is aryl or heteroaryl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₃ and so forth.

Whenever the terms “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall beinterpreted as including those limitations given above for “alkyl” and“aryl”. Alkyl or cycloalkyl substituents shall be recognized as beingfunctionally equivalent to those having one or more degrees ofunsaturation. Designated numbers of carbon atoms (e.g. C₁₋₁₀) shallrefer independently to the number of carbon atoms in an alkyl, alkenylor alkynyl or cyclic alkyl moiety or to the alkyl portion of a largersubstituent in which the term “alkyl” appears as its prefix root.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “halogen” or “halo” shall include iodine,bromine, chlorine and fluorine.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent —COOH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “aminosulfonyl” shall refer to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” shall refer to the substituent—C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the substituent —S—.

As used herein, the term “sulfenyl” shall refer to the substituent—S(O)—.

As used herein, the term “sulfonyl” shall refer to the substituent—S(O)₂—.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the term “biohydrolyzable ester” is an ester of a drugsubstance (in this invention, a compound of Formula (I)) which either a)does not interfere with the biological activity of the parent substancebut confers on that substance advantageous properties in vivo such asduration of action, onset of action, and the like, or b) is biologicallyinactive but is readily converted in vivo by the subject to thebiologically active principle. The advantage is that, for example, thebiohydrolyzable ester is orally absorbed from the gut and is transformedto (I) in plasma. Many examples of such are known in the art and includeby way of example lower alkyl esters (e.g., C₁-C₄), lower acyloxyalkylesters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylacylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drugsubstance (in this invention, a compound of general Formula (I)) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable amide is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl amides, α-amino acid amides,alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides andbiohydrolyzable esters and also encompasses a) compounds in which thebiohydrolyzable functionality in such a prodrug is encompassed in thecompound of Formula (I): for example, the lactam formed by a carboxylicgroup in R₂ and an amine in R₄, and b) compounds which may be oxidizedor reduced biologically at a given functional group to yield drugsubstances of Formula (I). Examples of these functional groups include,but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like.

The term “pharmacologically effective amount” or shall mean that amountof a drug or pharmaceutical agent that will elicit the biological ormedical response of a tissue, animal or human that is being sought by aresearcher or clinician. This amount can be a therapeutically effectiveamount. The term “therapeutically effective amount” shall mean thatamount of a drug or pharmaceutical agent that will elicit thetherapeutic response of an animal or human that is being sought.

The term “treatment” or “treating” as used herein, refers to the fullspectrum of treatments for a given disorder from which the patient issuffering, including alleviation of one, most of all symptoms resultingfrom that disorder, to an outright cure for the particular disorder orprevention of the onset of the disorder.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds ofFormula (I) along with methods for the preparation of compounds ofFormula (I). Unless otherwise indicated, variables refer to those forFormula (I).

An aldehyde (1) (Scheme 1) may be condensed with a diamine compound (2)in a solvent such as ethanol at a temperature of from 25 to 100 degreesCelsuis, to obtain the product benzimidazole (3), where the intermediateadduct undergoes spontaneous oxidation. Alternately, the acid (1a) maybe coupled with the diamine compound (2) employing a reagent such asHBTU to afford (2a). The reaction may also afford some of the compoundwhere the carboxylic acid has coupled to the secondary aniline nitrogen.Either product (2a) may be cyclized to (3). One nonlimiting method is toheat (2a) in a solvent such as acetic acid at a temperature of from 25to 100 degrees Celsuis, to obtain the cyclized product (3). Ar₁ is agroup such as but not limited to an optionally substituted aryl orheteroaryl ring system.

Where R₅₂ is aryl, heteroaryl, or contains an aryl or heteroaryl grouppossessing a phenolic substituent, or where R₅₂ possesses a freehydroxyl group, an aldehyde of formula (4) (Scheme 2) may be treatedwith an optionally substituted alkyl halide R₅₁-LG₁ and a base such aspotassium carbonate, in a solvent such as DMF, at a temperature of from0 to 120° C., to afford (5). LG₁ represents a nucleofugal group such asiodide, bromide, methanesulfonate, or toluenesulfonate (Scheme 2). WhereR₅₃ in (6) represents an aryl or heteroaryl ring system, directtreatment of (6) in the presence of a base such as DIEA or TEA with anaryl or heteroaryl phenol Ar₂—OH provides (7), where the Ar₂—O—substituent is bonded to the same atom as the F in (6).

In Scheme 3, an aldehyde (8) processing two free hydroxyl groups , twofree phenolic groups, of a combination of phenolic and hydroxyl groupsmay be treated with two equivalents of an alkylating agent R₅₁-LG₁, inthe presence of a suitable base such as potassium carbonate or DIEA, ina solvent such as DMF, to afford (9). Alternately, where R₅₃ is an arylring posessing ortho and para hydroxyl groups relative to the aldehydegroup, treatment of (8) with one equivalent of base and an alkylatingagent R₅₁-LG₁ in the presence of a suitable base such as DIEA ofpotassium carbonate, followed by treatment with a second alkylatingagent R₅₄-LG₂ in the presence of base, affords (10). The ortho, paradifluoro aldehyde (11), where R₅₃ is a heteroaryl or aryl ring, may betreated with an alcohol R₅₅—OH in the presence of base such as DIEA,followed by treatment with a phenol Ar₃—OH in the presence of a basesuch as DIEA or potassium carbonate, to afford (12).

Scheme 4 describes the synthesis of substituted arylenediamines.

In Scheme 4, an ortho-fluoro nitrophenol such as (13) may be alkylatedwith an alkyl halide or other alkylating agent R₅₆-LG₁, in the presenceof an alkali metal carbonate as base in a solvent such as DMF oracetonitrile. LG₁ may represent a nucleofugal group such as iodide,bromide, methanesulfonate, and the like. In this transformation, R₅₆ isa group such as but not limited to alkyl. The intermediate may betreated with an amine R₂—NH₂ in the presence or absence of a tertiaryamine base, in a solvent such as THF, at a temperature of from 0° C. to100° C., to afford (14). Reduction of the nitro group in (14) may beaccomplished by treatment of (14) in acidic or neutral ethanol withstannous chloride at a temperature of from 25° C. to 100° C. to affordthe aniline (15). Alternately, (14) may be reduced by treatment of (14)with a noble metal catalyst such as palladium on charcoal and a hydrogensource such as gaseous hydrogen or ammonium formate, in a solvent suchas ethanol, at a temperature of from 25° C. to 80° C., to afford (15).The difluoronitroaromatic compound (16) may be employed in similarmanner, where in (16), one fluoro is ortho to the nitro group. Treatmentof (16) with the one equivalent of amine R₂—NH₂ gives preferentialsubstitution of the ortho fluorine. The second fluorine in theintermediate may be substituted by an alcohol R₅₇—OH to afford (17). Inthis instance, R₅₇ may also be aryl. Reduction of the nitro group in(17) as before with stannous chloride provides (18). Ar₄ represents agroup such as but not limited to aryl or heteroaryl.

Scheme 5 describes synthesis of aryl diamines. The2,4,6-trifluoronitroaromatic compound (19) may be treated with oneequivalent of an amine R₂—NH₂ to afford the product of substitution atone ortho fluoro; excess R₅₈—OH may then be employed in the presence ofa base such as potassium tert-butoxide or sodium hydride to afford (20).Reduction of the nitro group as for Scheme 4 affords the aniline (21).Similarly, a 3,5-difluorophenolic aromatic compound (22) may be nitratedunder strong nitrating conditions, e.g. fuming nitric acid, to affordthe ortho nitro phenol (23) along with the para nitrophenol (24). Eachindividually may be processed by sequential phenol alkylation, orthofluoro displacement by R₂—NH₂, and para or ortho fluorodisplacement byR₅₈—OH, to afford (25) and (26) after reduction, following chemistriesin the preceding general procedures. Ar₅ represents a group such as butnot limited to aryl or heteroaryl.

Scheme 6 describes the synthesis of mono and di alkoxy -substitutedaminoaryl and aminoheteroaryl compounds. A fluoronitroaromatic (27),where F is preferably ortho or para to the nitro, may be treated with analcohol or phenol R₆₀—OH and a base such as potassium tert-butoxide orsodium hydride, to afford the ipso adduct. Reduction of the nitro groupto amino following preceding methods affords (28). Similarly,displacement of the fluoro groups in (29) with R₆₀—OH followed byreduction as before give (30). The nitro compound (31) may be treatedwith a base and R₆₁-LG₁ to afford the alkylation product, then treatedwith R₆₀—OH and a base, then reduced as above to give (32). Alternately,(33) may be processed similarly to give (32). Ar₆ represents a groupsuch as but not limited to aryl or heteroaryl.

Scheme 7 describes a general synthesis of imidazoles. An anilinecontaining a basic side chain (—O—R₆₂) (40) may be coupled with abromoketone containing a non-basic side chain (—O—R₆₃) (41) to give theaminoketone (42), which may then be treated with acetic acid, heat, analdehyde R₁—CHO, and ammonium acetate to afford (43). Alternately, (42)may be treated with an acid chloride R₁—COCl to afford (44), which maysubsequently be treated with ammonium acetate, acetic acid and heat toafford (43). Ar₇ and Ar₈ represent groups such as but not limited toaryl or heteroaryl.

Scheme 8 describes another general synthesis of imidazoles. An anilinecontaining a non-basic side chain (45) may be coupled with a bromoketonecontaining a basic side chain (46) to give the aminoketone (47), whichmay then be treated with acetic acid, heat, an aldehyde R₁—CHO, andammonium acetate to afford (48). Alternately, (42) may be treated withan acid chloride R₁—COCl to afford (49), which may subsequently betreated with ammonium acetate, acetic acid and heat to afford (43). Ar₇and Ar₈ represent groups such as but not limited to aryl or heteroaryl.

Scheme 9 describes another general synthesis of imidazoles. An anilinecontaining a basic side chain (40) may be coupled with a bromoketone(50) to give the aminoketone (51), which may then be treated with anacid chloride R₁—COCl to afford (52), which may subsequently be treatedwith ammonium acetate, acetic acid and heat to afford (53). The phenolis then alkylated with a alkylating agent R₆₃-LG₅ to generate thedesired imidazole (54). R₆₃ is a group such as but not limited tosubstituted alkyl, and LG₅ is a leaving group such as iodide ormethanesulfonate. Ar₇ and Ar₈ represent groups such as but not limitedto aryl or heteroaryl.

Scheme 10 describes another general synthesis of imidazoles. An anilinecontaining a hydrophobic side chain (40) may be coupled with abromoketone (55) to give the aminoketone (56), which may then be treatedwith an acid chloride R₁—COCl to afford (57), which may subsequently betreated with ammonium acetate, acetic acid and heat to afford (58). Thephenol is then deprotected; PG₁ may be a group sych as but not limitedto benzyl, which may be removed with treatment with hydrogen overpalladium on carbon. The free phenolic group is subsequently alkylatedwith an alkylating agent R₆₃-LG₅ to generate the desired imidazole (59).R₆₃ is a group such as but not limited to substituted alkyl, and LG₅ isa leaving group such as iodide or methanesulfonate.

Scheme 11 describes the synthesis of diones or bromoketones. A arylketone (60) may be treated with base and an alkylating agent R₆₄-LG₆ togenerate the phenyl ether. R₆₄ is a group such as but not limited tosubstituted alkyl, and LG₆ is a leaving group such as iodide ormethanesulfonate. The product may be brominated with a reagent such asbut not limited to pyrrolidinium hydrotribromide, to (61) and thebromide may be oxidized by treatment with DMSO to afford (62). (63) maybe treated with Ar₁₀—OH and base, followed by bromination, to afford(64). Oxidation as before gives the dione (65). Ar₉ is a group such asbut not limited to aryl or heteroaryl.

Scheme 12 describes the synthesis of imidazoles. (66) may be treatedwith (67) and an aldehyde R₁—CHO to afford (68). Alternately, (66) maybe coupled with the bromoketone (70) to give the aminoketone (71), whichmay be treated with acetic acid, heat, an aldehyde R₁—CHO, and ammoniumacetate to afford (68). Ar₁₁ and Ar₁₂ are groups such as but not limitedto aryl or heteroaryl.

Scheme 13 describes the synthesis of imidazoles. A dione (72) may betreated with R₁—CHO and ammonium acetate -acetic acid to afford (74).Alternately, an amine R₂—NH₂ may be used in place of ammonium acetate togive (75).

Scheme 14 describes another synthesis of imidazoles. (76) may be coupledwith the bromoketone (77) to give the aminoketone (78), which may betreated with acetic acid, heat, an aldehyde R₁—CHO, and ammonium acetateto afford (80). Alternately, (78) may be treated with an acid chlorideR₁—COCl to afford (79), which may subsequently be treated with ammoniumacetate, acetic acid and heat to afford (80). The group R₆₈ may be anamino protecting group, such as BOC, which may be removed by treatmentof (80) with TFA. The amine may be directly alkylated or reductivelyalkylated by methods known in the art. For example, treatment of the NHcompound with acetaldehyde and sodium cyanoborohydride in a solvent suchas acetic acid affords (80) where R₆₈ is ethyl. Ar₁₂ is a group such asbut not limited to aryl or heteroaryl.

Scheme 15 describes the synthesis of imidazoles. A dione (81) may betreated with R₁—CHO and an amine (76) in acetic acid, in the presence ofammonium acetate, at a temperature of from 50 to 140° C., to afford(83). If the group R₆₈ is an amine protecting group, then saidprotecting group may be removed and the nitrogen alkylated as describedin Scheme 14.

The term “amino protecting group” as used herein refers to substituentsof the amino group commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include the formyl group, thetrityl group, the phthalimido group, the trichloroacetyl group, thechloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blockinggroups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluoyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (“BOC”),2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; thebenzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, thediphenylphosphine oxide group and like amino-protecting groups. Thespecies of amino-protecting group employed is not critical so long asthe derivatized amino group is stable to the condition of subsequentreaction(s) on other positions of the compound of Formula (I) and can beremoved at the desired point without disrupting the remainder of themolecule. Preferred amino-protecting groups are the allyloxycarbonyl,the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl groups.Similar amino-protecting groups used in the cephalosporin, penicillinand peptide art are also embraced by the above terms. Further examplesof groups referred to by the above terms are described by J. W. Barton,“Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., PlenumPress, New York, N.Y., 1973, and T. W. Greene, “Protective Groups inOrganic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. Therelated term “protected amino” or “protected amino group” defines anamino group substituted with an amino-protecting group discussed above.

The term “hydroxyl protecting group” as used herein refers tosubstituents of the alcohol group commonly employed to block or protectthe alcohol functionality while reacting other functional groups on thecompound. Examples of such alcohol -protecting groups include the2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, thetrichloroacetyl group, urethane-type blocking groups such asbenzyloxycarbonyl, and the trialkylsilyl group, examples of such beingtrimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl,triiospropylsilyl and thexyldimethylsilyl. The choice ofalcohol-protecting group employed is not critical so long as thederivatized alcohol group is stable to the condition of subsequentreaction(s) on other positions of the compound of the formulae and canbe removed at the desired point without disrupting the remainder of themolecule. Further examples of groups referred to by the above terms aredescribed by J. W. Barton, “Protective Groups In Organic Chemistry”, J.G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1981. The related term “protected hydroxyl” or “protected alcohol”defines a hydroxyl group substituted with a hydroxyl-protecting group asdiscussed above.

The term “carboxyl protecting group” as used herein refers tosubstituents of the carboxyl group commonly employed to block or protectthe —OH functionality while reacting other functional groups on thecompound. Examples of such alcohol -protecting groups include the2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, theallyl group, the trimethylsilylethoxymethyl group, the2,2,2-trichloroethyl group, the benzyl group, and the trialkylsilylgroup, examples of such being trimethylsilyl, tert-butyldimethylsilyl,phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. Thechoice of carboxyl protecting group employed is not critical so long asthe derivatized alcohol group is stable to the condition of subsequentreaction(s) on other positions of the compound of the formulae and canbe removed at the desired point without disrupting the remainder of themolecule. Further examples of groups referred to by the above terms aredescribed by J. W. Barton, “Protective Groups In Organic Chemistry”, J.G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1981. The related term “protected carboxyl” defines a carboxylgroup substituted with a carboxyl-protecting group as discussed above.

The general procedures used in the methods of the present invention aredescribed below.

Methods

LC-MS data is obtained using gradient elution on a Waters 600 controllerequipped with a 2487 dual wavelength detector and a Leap TechnologiesHTS PAL Autosampler using an YMC Combiscreen ODS-A 50×4.6 mm column. Athree minute gradient is run from 25% B (97.5% acetonitrile, 2.5% water,0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100%B. The mass spectrometer used is a Micromass ZMD instrument. All data isobtained in the positive mode unless otherwise noted. ¹H NMR and ¹³C NMRdata is obtained on a Varian 400 MHz spectrometer.

Abbreviations used in the Examples are as follows:

APCI=atmospheric pressure chemical ionizationBOC=tert-butoxycarbonylBOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphoniumhexafluorophosphated=dayDIAD=diisopropyl azodicarboxylateDCC=dicyclohexylcarbodiimideDCM=dichloromethaneDIC=diisopropylcarbodiimideDIEA=diisopropylethylamine

DMA=N,N-dimethylacetamide

DMAP=dimethylaminopyridineDME=1,2 dimethoxyethane

DMF=N,N-dimethylformamide

DMPU=1,3-dimethypropylene ureaDMSO=dimethylsulfoxideEt=ethyliPr=isopropylBn=benzylMe=methyltBu=tert-butylPr=propylBu=butyliBu=isobutylEDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochlorideEDTA=ethylenediamine tetraacetic acidELISA=enzyme-linked immunosorbent assayESI=electrospray ionizationether=diethyl etherEtOAc=ethyl acetateFBS=fetal bovine serumg=gramh=hourHBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHMPA=hexamethylphosphoric triamideHOBt=1-hydroxybenzotriazoleHz=hertzi.v.=intravenouskD=kiloDaltonL=literLAH=lithium aluminum hydrideLDA=lithium diisopropylamideLPS=lipopolysaccharideM=molarm/z=mass to charge ratiombar=millibarMeOH=methanolmg=milligrammin=minutemL=millilitermM=millimolarmmol=millimolemol=molemp=melting point

MS=mass spectrometry

N=normalNMM=N-methylmorpholine, 4-methylmorpholineNMR=nuclear magnetic resonance spectroscopyp.o.=per oralPS-carbodiimide=N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrenePBS=phosphate buffered saline solutionPMA=phorbol myristate acetateppm=parts per millionpsi=pounds per square inchR_(f)=relative TLC mobilityrt=room temperatures.c.=subcutaneousSPA=scintillation proximity assayTEA=triethylamineTFA=trifluoroacetic acidTHF=tetrahydrofuranTHP=tetrahydropyranylTLC=thin layer chromatographyTMSBr=bromotrimethylsilane, trimethylsilylbromideT_(r)=retention timeGeneral synthesis of Monoalkoxybenzaldehydes:

General Procedure A

To a stirred solution of a 2-, 3-, or 4-hydroxybenzaldehyde (2 mmol) inDMF (6 mL) at rt solid K₂CO₃ (4 mmol) is added. An alkyl halide ormesylate (prepared from the corresponding alcohol and methanesulfonylchloride) (2.2 mmol) is added to the reaction mixture and heated to 80°C. until the reaction is complete as indicated by TLC or HPLC. Aftercooling to rt, the reaction mixture is poured into EtOAc (20 ml) andwashed with water (2×10 ml) and brine (15 ml). The organic layer isdried over magnesium sulfate and after removal of the drying agent, thesolvent is removed under high vacuum to afford the desired product. Thecrude product may be used for further transformation without anypurification or after purifying using silica gel column chromatography.

General Synthesis of Monoaryloxybenzaldehydes: General Procedure B

To a stirred solution of a 2-, 3-, or 4-fluorobenzaldehyde (2 mmol) inDMF (6 mL) at rt requisite phenol (2.2) is added followed by solid K₂CO₃(3 mmol). The reaction mixture is heated to 100° C. until the reactionis complete as indicated by TLC or HPLC. After cooling to rt, thereaction mixture is poured into EtOAc (20 ml) and washed with water(2×10 ml) and brine (15 ml). The organic layer is dried over magnesiumsulfate and after removal of the drying agent, the solvent is removedunder high vacuum to afford the desired product. The crude product maybe used for further transformation without any purification or afterpurifying using silica gel column chromatography.

General Synthesis of Homosubstituted 2,4-dialkoxybenzaldehydes:

General Procedure C

To a stirred solution of 2,4-dihydroxybenzaldehyde (2 mmol) in DMF (8mL) at it solid Cs₂CO₃ (6 mmol) is added. An alkyl halide or mesylate(prepared from the corresponding alcohol and methanesulfonyl chloride,see General Procedure P2) (4.4 mmol) is added to the reaction mixtureand heated to 80° C. until the reaction is complete as indicated by TLCor HPLC. After cooling to rt, the reaction mixture is poured into EtOAc(20 ml) and washed with water (2×10 ml) and brine (15 ml). The organiclayer is dried over magnesium sulfate and after removal of the dryingagent, the solvent is removed under high vacuum to afford the desiredproduct. The crude product may be used for further transformationwithout any purification or after purifying using silica gel columnchromatography.

General Synthesis of Heterosubstituted 2,4-dialkoxybenzaldehydes:

General Procedure D1

To a stirred solution of 2,4-dihydroxybenzaldehyde (2.2 mmol) in DMF (5mL) at it solid KHCO₃ (2.2 mmol) is added. An alkyl halide or mesylate(prepared from the corresponding alcohol and methanesulfonyl chloride,see General Procedure P2) (2.0 mmol) is added to the reaction mixtureand heated at 130° C. for 4 h. After cooling to rt, the reaction mixtureis treated with cold H₂O (15 mL), and extracted with EtOAc (2×10 mL).The combined organic layers is washed with brine, and dried over sodiumsulfate. The crude product is purified by flash chromatography toprovide the 2-hydroxy-4-alkoxybenzaldehyde intermediate.

General Procedure D2

To a stirred solution of aforementioned 2-hydroxy-4-alkoxybenzaldehydeintermediate (2 mmol) in DMSO (5 mL) at rt solid Cs₂CO₃ (3 mmol) isadded. An alkyl halide or mesylate (prepared from the correspondingalcohol and methanesulfonyl chloride, see General Procedure P2) (3 mmol)is added to the reaction mixture and heated to 90° C. until the reactionis complete as indicated by TLC or HPLC. After cooling to rt, thereaction mixture is treated with cold H₂O (15 mL), and extracted withEtOAc (2×10 mL). The combined organic layers is washed with H₂O (10 mL)and brine (10 mL) and dried over sodium sulfate. After removal of thedrying agent, the solvent is removed under high vacuum to afford thedesired product. The crude product may be used for furthertransformation without any purification or after purifying using silicagel column chromatography.

General Synthesis of 2-alkoxy-4-aryloxybenzaldehydes:

General Procedure E

A solution of 2,4-difluorobenzaldehyde (2 mmol) in DMF (2 mL) is addeddropwise to a precooled (0° C.) solution of sodium alkoxide (2 mmol) inDMF (6 ml) [prepared by stirring a mixture of sodium hydride (2 mmol),and the corresponding alcohol (2 mmol) in DMF]. The resulting reactionmixture is warmed to it and stirred for an additional 3 h. To the samereaction vessel, solid potassium carbonate (2 mmol) and requisite phenol(2 mmol)) is introduced and the reaction mixture is heated at 90° C. inan oil bath for 24. After cooling to rt, the reaction mixture is pouredinto EtOAc (20 ml) and washed with water (2×10 ml) and brine (15 ml).The organic layer is dried over magnesium sulfate and after removal ofthe drying agent, the solvent is removed under high vacuum to afford thedesired product. The crude product may be used for furthertransformation without any purification or after purifying using silicagel column chromatography.

General Synthesis of Monoalkoxy Ortho-Phenylenediamines: Method A:General Procedure F1

To a stirred solution of 3-fluoro-4-nitrophenol (4 mmol) in DMF (6 mL)at it solid K₂CO₃ (8 mmol) is added. An alkyl halide or mesylate(prepared from the corresponding alcohol and methanesulfonyl chloride,see General Procedure P2) (4.4 mmol) is added to the reaction mixtureand heated to 80° C. until the reaction is complete as indicated by TLCor HPLC. After cooling to rt, the reaction mixture is poured into EtOAc(40 ml) and washed with water (2×20 ml) and brine (30 ml). The organiclayer is dried over magnesium sulfate and after removal of the dryingagent, the solvent is removed under vacuum to afford the desiredproduct. The crude product may be used for further transformationwithout any purification or after purifying using silica gel columnchromatography.

General Procedure F2

To a stirred solution of 2-fluoro-4-alkoxynitrobenzene (2 mmol) obtainedabove, TEA (4 mmol) in DMF (5 mL) is added dropwise a solution ofrequisite alkylamine (2.2 mmol) in DMF (2 mL) at rt within 15 min, andthen stirred at it for 5 h. The reaction mixture is treated with coldH₂O (10 mL), and extracted with EtOAc (2×15 mL), The combined organiclayers is washed with H₂O (10 mL) and brine (10 mL) and dried oversodium sulfate. After removal of the drying agent, the solvent isremoved under high vacuum to afford the desired2-alkylamino-4-alkoxynitrobenzene intermediate. The crude product may beused for further transformation without any purification or afterpurifying using silica gel column chromatography.

Method B: General Procedure G1

To a stirred solution of 2,4-difluoronitrobenzene (2 mmol), TEA (4 mmol)in DMF (5 mL) is added dropwise a solution of requisite alkylamine (2.2mmol) in DMF (2 mL) at it within 15 min, and then stirred at it for 5 h.The reaction mixture is treated with cold H₂O (10 mL), and extractedwith EtOAc (2×15 mL), The combined organic layers is washed with H₂O (10mL) and brine (10 mL) and dried over sodium sulfate. After removal ofthe drying agent, the solvent is removed under high vacuum to afford thedesired 2-alkylamino-4-fluoronitrobenzene. The crude product may be usedfor further transformation without any purification or after purifyingusing silica gel column chromatography.

General Procedure G2

To a stirred solution of 2-alkylamino-4-fluoronitrobenzene as obtainedabove (2.0 mmol) in anhydrous THF (4 mL), an alcohol (2.4 mmol) is addedfollowed by powdered KOBu^(t) (2.4 mmol) in one portion at rt and underthe N₂ stream. The reaction mixture is then refluxed until the reactionis complete as indicated by TLC or HPLC. After cooling to rt, thereaction mixture is treated with cold H₂O (15 mL), and extracted withEtOAc (2×10 mL). The combined organic layers is washed with brine, anddried over sodium sulfate. Evaporation of the solvent in vacuo afforded2-alkylamino-4-alkoxynitrobenzene intermediate. The crude product may beused for further transformation without any purification or afterpurifying using silica gel column chromatography.

Reduction of Monoalkoxy Nitrobenzenes: General Procedure H

The nitro intermediate (2 mmol) obtained above as in Method A or B isdissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C(10 mg) until the reaction is complete as indicated by TLC or HPLC. Thereaction mixture is then filtered through a celite pad to remove thecatalyst. The solvent is removed under high vacuum to afford the desireddiamine, which is used directly for further transformation withoutfurther purification.

General Procedure I

To a stirred solution of afforded 2-alkylamino-4-alkoxynitrobenzeneintermediate [as obtained in (b)](2 mmol) in EtOH (20 mL), SnCl₂.2H₂O (8mmol) is added and the mixture is refluxed until the reaction iscomplete as indicated by TLC or HPLC. After completion of the reduction,the solvent is removed in vacuo, and the residue is treated withsaturated NaHCO₃ to pH˜8. The resulting yellow suspension is extractedwith DCM (2×20 mL), washed with brine, and dried. The solvent is removedunder high vacuum to afford the desired diamine, which is used directlyfor further transformation without further purification.

General synthesis of homo disubstituted dialkoxyortho-phenylenediamines:

General Procedure J1

To a stirred solution of 2,4,6-trifluoronitrobenzene (3.0 mmol) andtriethylamine (6.0 mmol) in DMF (6 mL), a solution of alkyl amine (3.0mmol) in DMF (2 mL) is added dropwise at rt within 15 min, and thenstirred at rt for 5 h. The reaction mixture is treated with cold H₂O (10mL), and extracted with EtOAc (2×15 mL), The combined organic layers iswashed with H₂O (10 mL) and brine (10 mL) and dried over sodium sulfate.After removal of the drying agent, the solvent is removed under highvacuum to afford the desired 2-alkylamino-4,6-difluoronitrobenzene. Thecrude product may be used for further transformation without anypurification or after purifying using silica gel column chromatography.

General Procedure J2

To a stirred solution of 2-alkylamino-4,6-difluoronitrobenzene asobtained above (2.0 mmol) in anhydrous THF (4 mL), an alcohol (4.4 mmol)is added followed by powdered KOBu^(t) (4.4 mmol) in one portion at rtand under the N₂ stream. The reaction mixture is then refluxed until thereaction is complete as indicated by TLC or HPLC. After cooling to rt,the reaction mixture is treated with cold H₂O (15 mL), and extractedwith EtOAc (2×15 mL). The combined organic layers is washed with brine,and dried over sodium sulfate. Evaporation of the solvent in vacuoafforded 2-alkylamino-4,6-dialkoxynitrobenzene intermediate. The crudeproduct may be used for further transformation without any purificationor after purifying using silica gel column chromatography.

The nitro intermediate (2 mmol) obtained may be reduces to the aminocompound employing general procedures H or I.

General Synthesis of Hetero Disubstituted DialkoxyOrtho-Phenylenediamines: General Procedure J3

To a stirred solution of 3,5-difluorophenol (3 g; 17 mmol) indichloromethane (30 mL) at 0° C., conc. HNO₃ (2.5 mL) is added dropwiseover 10 min. The reaction mixture is then stirred at 0° C. for 60 min atwhich the nitration is complete as indicated by TLC. After the reactionis complete cold H₂O (30 mL) is added to the reaction flask and stirred.The contents are then poured into a separatory funnel and the layersremoved. The aqueous layer is then extracted with EtOAc (2×30 mL) andthe combined organic layers are dried over magnesium sulfate. Afterremoval of the drying agent, the solvent is removed under vacuum to thecrude product mixture is purified using silica gel column chromatographyto provide the nitrodifluorophenol.

General Procedure J4

To a stirred solution of 3,5-difluoro-4-nitrophenol (4 mmol) in DMF (6mL) at rt solid K₂CO₃ (8 mmol) is added. An alkyl halide or mesylate(prepared from the corresponding alcohol and methanesulfonyl chloride,see General Procedure P2) (4.4 mmol) is added to the reaction mixtureand heated to 80° C. until the reaction is complete as indicated by TLCor HPLC. After cooling to rt, the reaction mixture is poured into EtOAc(40 ml) and washed with water (2×20 ml) and brine (30 ml). The organiclayer is dried over magnesium sulfate and after removal of the dryingagent, the solvent is removed under vacuum to afford the desiredproduct. The crude product may be used for further transformationwithout any purification or after purifying using silica gel columnchromatography.

General Procedure J5

To a stirred solution of 2,6-difluoro-4-alkoxynitrobenzene obtainedabove (3.0 mmol) and triethylamine (6.0 mmol) in DMF (6 mL), a solutionof alkyl amine (3.0 mmol) in DMF (2 mL) is added dropwise at rt within15 min, and then stirred at rt for 5 h. The reaction mixture is treatedwith cold H₂O (10 mL), and extracted with EtOAc (2×15 mL). The combinedorganic layers is washed with H2O (10 mL) and brine (10 mL) and driedover sodium sulfate. After removal of the drying agent, the solvent isremoved under high vacuum to afford the desired2-alkylamino-4-alkoxy-6-fluoronitrobenzene. The crude product may beused for further transformation without any purification or afterpurifying using silica gel column chromatography.

General Procedure J6

To a stirred solution of 2-alkylamino-4-alkoxy-6-fluoronitrobenzene asobtained above (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1Msolution of an alkoxide (2.2 mmol) in THF (may be generated by addingthe corresponding alcohol to a 1M solution of KOBU^(t) in THF) is addeddropwise and under the N₂ stream. The reaction mixture is maintained at0° C. until the reaction is complete as indicated by TLC or HPLC. Thereaction mixture is then treated with cold H₂O (15 mL), and extractedwith EtOAc (2×15 mL). The combined organic layers is washed with brine,and dried over sodium sulfate. Evaporation of the solvent in vacuoafforded the desired hetero dialkoxy substituted nitro intermediate. Thecrude product may be used for further transformation without anypurification or after purifying using silica gel column chromatography.

General Procedure J7

The nitro intermediate (2 mmol) obtained above is dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until thereaction is complete as indicated by TLC or HPLC. The reaction mixtureis then filtered through a celite pad to remove the catalyst. Thesolvent is removed under high vacuum to afford the desired heterodisubstituted dialkoxy ortho-phenylenediamine.

General Procedure for Synthesis of Benzimidazoles: General Procedure K

A solution of an ortho phenylenediamine (2 mmol) and an appropriate arylaldehyde in ethanol is refluxed until the reaction is complete asindicated by TLC or HPLC. The solvent is removed in vacuo and theresidue obtained is purified by silica gel column chromatography toafford the desired 2-arylbenzimidazole.

General Procedure for Synthesis of Monoalkoxyanilines: Method A: GeneralProcedure L1

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium alkoxide (2.2 mmol) inTHF (may be generated by adding the corresponding alcohol to a 1Msolution of KOBu^(t) in THF) is added dropwise and under the N₂ stream.The reaction mixture is stirred at 0° C. until completion, as indicatedby TLC or HPLC. The reaction mixture is then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct could be used directly for further transformation without anypurification, or after purifying using silica gel column chromatography.

Method B: General Procedure M1

To a stirred solution of 4-nitrophenol (2 mmol) in DMF (6 mL) at rt,solid potassium carbonate (4 mmol) is added. An alkyl halide or mesylate(prepared from the corresponding alcohol and methanesulfonyl chloride,see General Procedure P2) (2.2 mmol) is then added to the reactionmixture and heated to 80° C. until completion, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture is then treated withcold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combinedorganic layers were washed with brine and dried over sodium sulfate.Evaporation of the solvent in vacuuo afforded the desired4-alkoxynitrobenzene. The crude product could be used directly forfurther transformation without any purification, or after purifyingusing silica gel column chromatography.

General Procedure for Synthesis of Homo Disubstituted Alkoxy-Anilines:Method C General Procedure N1

To a stirred solution of 2,4-difluoronitrobenzene (2.0 mmol) inanhydrous THF (4 mL) at 0° C., an alcohol (4.4 mmol) is added followedby powdered potassium t-butoxide (4.4 mmol) in one portion under a N₂stream. The reaction mixture is then warmed to rt and heated underreflux until completion, as indicated by TLC or HPLC. After cooling tort, the reaction mixture is treated with cold H₂O (15 mL), and extractedwith EtOAc (2×15 mL). The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of the solvent in vacuuoafforded the 2,4-dialkoxynitrobenzene. The crude product could then beused for further transformation without any purification, or afterpurifying using silica gel column chromatography.

General Procedure for Synthesis of Alkoxy-Anilines: General Procedure O2

To a stirred solution of 4-alkoxy-2-fluoronitrobenzene obtained above(2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of analkoxide (2.2 mmol) in THF (may be generated by adding the correspondingalcohol to a 1M solution of potassium t-butoxide in THF) is addeddropwise and under a N₂ stream. The reaction mixture is maintained at 0°C. until completion, as indicated by TLC or HPLC. The reaction mixtureis then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15mL). The combined organic layers were washed with brine, and dried oversodium sulfate. Evaporation of the solvent in vacuuo afforded thedesired hetero-substituted dilkoxynitrobenzene. The crude product may beused for further transformation without any purification or afterpurifying using silica gel column chromatography.

Method E: General Procedure P1

To a stirred solution of a 2-nitro-5-fluorophenol (2.0 mmol) inanhydrous THF (4 mL) at 0° C., an alcohol (2.2 mmol) is added followedby powdered potassium t-butoxide (4.2 mmol) in one portion under a N₂stream. The reaction mixture is then warmed up to rt and heated underreflux until completion, as indicated by TLC or HPLC. After cooling tort, the crude reaction mixture is treated with an alkyl halide ormesylate (2.2 mmol, prepared from the corresponding alcohol andmethanesulfonyl chloride) and heated under reflux until completion, asindicated by TLC or HPLC. The reaction mixture is then cooled to rt,treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). Thecombined organic layers were washed with brine, and dried over sodiumsulfate. Evaporation of the solvent in vacuuo afforded thehetero-substituted dilkoxynitrobenzene. The crude product may be usedfor further transformation without any purification or after purifyingusing silica gel column chromatography.

General Procedure P2

A primary or secondary alcohol (20 mmol, 1 eq) is dissolved in DCM (25mL), TEA (40 mmol, 2 eq) is added and the mixture is cooled to 0° C. Tothis mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) is added slowlywith stirring and the reaction mixture is stirred at 0° C. for an hourand at rt for another hour (until the reaction is complete by HPLC). Thesolvent is removed and to this saturated aqueous sodium bicarbonate isadded. The product is extracted with EtOAc (3×) and washed with sodiumbicarbonate and water. The solvent is removed in vacuuo to afford theproduct methanesulfonate.

General Procedure for Synthesis of Alkyl Phenones; Method F: GeneralProcedure Q1

To a stirred solution of 4′-hydroxyacetophenone (1.2 mmol) in DMF (10mL) at rt, solid potassium carbonate (3.0 mmol) is added. An alkylhalide or mesylate (prepared from the corresponding alcohol andmethanesulfonyl chloride, see General Procedure P2) (1.0 mmol) is addedto the reaction mixture and heated to 80° C. until completion, asindicated by TLC or HPLC. After cooling to rt, the reaction mixture isquenched by removing solvent in vacuuo and treating the residue withsaturated sodium bicarbonate. The aqueous layer is poured into EtOAc (20ml) and washed with H₂O (2×10 ml) and brine (15 ml). The organic layeris dried over magnesium sulfate, and the solvent is removed in vacuuo toafford the desired product. The crude alkylated product may be used forfurther transformation without any purification or after purifying usingsilica gel column chromatography.

Method G: General Procedure Q2

To a stirred solution of an alcohol (75 mmol) in DMSO (80 mL) at rt,solid cesium carbonate (150 mmol) is added. 4′-fluoro-alkylphenone (50mmol) is added to the reaction mixture and heated to 90° C. untilcompletion, as indicated by TLC or HPLC. After cooling to rt, thereaction mixture is treated with saturated sodium bicarbonate (150 ml).The aqueous layer is extracted with diethyl ether (4×100 ml). Theorganic layer is washed with H₂O (2×10 ml) and brine (15 ml). Theorganic layer is dried over magnesium sulfate, and the solvent isremoved in vacuuo to afford the desired alkoxy acetophenone. The crudealkylated acetophenone may be used for further transformation withoutany purification or after purifying using silica gel columnchromatography.

General Procedure for N-Aryl Imidazoles: Method H: General Procedure R1

To a stirred solution of alkoxyacetophenone (2 mmol) in anhydrous MeOH(5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.) is added. Thereaction mixture is stirred under nitrogen at 0° C. for 1 h and isallowed to warm to ambient temperature until completion, as indicated byTLC or HPLC. The solvent is then removed in vacuuo and the crudealpha-bromoacetophenone is used for further transformation.

General Procedure R2

To a stirred solution of an alkoxy aniline (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) diisopropylethylamine (3 eq. 6 mmol) is added,followed by a slow addition of the alpha-bromoacetophenone describedabove (1.6 mmol). The reaction mixture is stirred under nitrogen at rtuntil completion, as indicated by TLC or HPLC. The reaction mixture isthen diluted with cold H₂O and the product is isolated in EtOAc. Thecombined organic layers were washed with brine and dried over sodiumsulfate. Evaporation of solvent in vacuuo afforded the desired product.The crude alkylated aniline is purified by chromatography (Silica gel).Pure product obtained from 2-4% MeOH/DCM (yield ˜50-60%).

General Procedure R3

To a stirred solution of alkylated aniline described above (2 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 6 mmol) is added, followed bya slow addition of an acid chloride or anhydride (3 eq., 6 mmol). Thereaction mixture is stirred under nitrogen at 0° C. for 1 h and allowedto warm to ambient temperature until completion, as indicated by TLC orHPLC. The solvent is removed in vacuuo, and the crude amide is used forfurther transformation.

General Procedure R4

To a stirred solution of the amide described above (2 mmol) in AcOH (2mL), ammonium acetate (excess, ˜20 eq.) is added. The reaction mixtureis stirred at 90° C. overnight. The reaction mixture is then cooled downand neutralized with saturated sodium bicarbonate solution. Usualextractive work up with EtOAc gave the product imidazole, which ispurified by column chromatography (Silica gel). Pure product is obtainedfrom 4-6% MeOH/DCM (yield 40-50%).

General Procedure S1

To a stirred solution of an alkoxy aniline (2 mmol) in DCM (4 mL) at rt,TEA (2.5 mmol) is added followed by an acid chloride or anhydride (2.5mmol). The reaction mixture is stirred under nitrogen at rt untilcompletion, as indicated by TLC or HPLC. The reaction mixture is treatedwith saturated aqueous sodium bicarbonate solution (5 mL), thenextracted with EtOAc (2×15 mL). The combined organic layers were washedwith H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporationof the solvent in vacuuo afforded the anilide. The crude product is usedfor further transformation.

General Procedure S2

To a stirred solution of the anilide (2 mmol) obtained as above inanhydrous THF (4 mL) solid sodium hydride (60% dispersion in oil; 2.2mmol) is added in portions. After the addition, a solution of abromo-acetophenone (2.2 mmol) (prepared as described earlier) inanhydrous THF (2 mL) is added to the reaction mixture. The reaction isthen allowed to proceed at rt or heated under reflux as needed. Uponcompletion of the reaction, EtOAc (20 mL) is added to the reactionmixture followed by H₂O (10 mL). The organic layer is washed with H₂O(2×15 mL) and brine, and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the N-alkylated anilide. The crude productmay be used for further transformation.

General Procedure S3

To a stirred solution of the N-alkylated anilide (1 mmol) obtained asabove in AcOH (3 mL), solid NH₄OAc (20 mmol) is added in one portion.The reaction mixture is then heated to 100° C. overnight. The reactionmixture is cooled to rt, and treated with saturated aqueous sodiumbicarbonate solution while stirring to until the pH is 7-8. The contentswere extracted with EtOAc (2×15 mL). The combined organic layers iswashed with H₂O (2×15 mL) and brine, and dried over sodium sulfate.Evaporation of the solvent in vacuuo afforded the desired N-arylimidazole. The crude product is purified using silica gel columnchromatography.

General Procedure T1

4N hydrogen chloride in dioxane solution (4 mmol) is added to a mixtureof BOC -amino compound (1 mmol) in anhydrous DCM (5 mL), and the mixtureis stirred at rt until complete. Evaporation of the solvents in vacuoafforded deprotected amine hydrochloride.

General Procedure T2

A benzyl alkyl ether, benzyl ester, or a benzyl phenyl ether isdissolved in MeOH and hydrogenated in the presence of 10% Pd/C catalystuntil the reaction is complete. reaction mixture is then filteredthrough a celite pad to remove the catalyst. Evaporation of the solventin vacuo afforded the alcohol, carboxylic acid, or phenol, respectively.

General Procedure T3

A phenol (0.2 mmol) in anhydrous DMF (5 mL) is alkylated by a bromide ora mesylate (0.3 mmol) at rt (for a bromide, 60% NaH as base) or at 90°C. (for a mesylate, K₂CO₃ as base). The reaction is quenched by addingsat. NaHCO₃. The resulting mixture is extracted with EtOAc washed withbrine and dried. The crude product is purified by silica gel columnchromatography if desired.

Example 11-Butyl-2-(3-cyclohexylmethoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

Hydroxy benzimidazole was formed employing1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (synthesizedvia General Procedures G1 and G2 and H) (2.92 g; 10 mmol) and3-hydroxybenzaldehyde (1.34 g, 11 mmol) in ethanol (20 mL) following thegeneral procedure K. The crude product was purified by silica gel columnchromatography using 2% MeOH in DCM (3.2 g).

MS m/z 396 (M+H)⁺

A solution of above mentioned hydroxybenzimidazole compound (39.4 mg,0.1 mmol) in THF (2 ml) was added cyclohexylmethyl bromide (19.5 mg,0.11 mmol) and NaH (0.8 mg, 60% , 0.12 mmol) at 0° C. The resultingreaction mixture was warmed to rt and stirred for additional 12 h. Themixture was quenched with brine and extracted into EtOAc (2×10 mL).Combined organic EtOAc extracts were dried over sodium sulfate andconcentrated to give compound which was purified by silica gel columnchromatography using dichloromethane and 2% methanol in dichloromethaneas eluent, to give N—BOC compound, which was subjected to GeneralProcedure T1 affording1-butyl-2-(3-cyclohexylmethoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazoleas a hydrochloride salt, 36.8 mg.

MS m/z 491 (M+H)⁺

Example 2(3-(3-butyl-2-(3-,5-di-tert-butyl-2-methoxy-phenyl)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine

This compound was prepared according to the general procedure K byrefluxing a mixture of 3,5-di-t-butyl-5-methoxybenzaldehyde (100 mg) andN²-Butyl-4-(3-diethylamino-propoxy)-benzene-1,2-diamine (synthesized viaGeneral Procedures G1 and G2 and H) (50 mg) in ethanol overnight.Ethanol was removed in vacuo and the residue was purified by silica gelchromatography using 5% MeOH in DCM to give(3-(3-butyl-2-(3-,5-di-tert-butyl-2-methoxy-phenyl)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine(45.0 mg).

MS: m/z 522 (M+H)⁺

Example 3(2-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-3H-benzimidazol-5-yloxy-ethyl)-diisopropyl-amine

A solution of 2-(n-butylamino)-4-(2-diisopropylaminoethoxy)aniline(synthesized via General Procedures G1 and G2 and H) (61.4 mg, 0.2 mmol)and (3-(4-tert-butyl-phenoxy)-benzaldehyde (synthesized via GeneralProcedure B) (56 mg, 0.22 mmol) in ethanol (2 mL) was condensedfollowing General Procedure K. The crude product was purified by silicagel column chromatography using 10% MeOH in DCM with a gradual incrementof triethylamine (0.2 to 1.0%) as eluent to afford(2-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-3H-benzimidazol-5-yloxy-ethyl)-diisopropyl-amine(54 mg).

MS m/z 542 (M+H)+

Example 4(3-{-4-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-hydroxybenzaldehyde (20 mmol) in DMSO (80 mL)at rt, solid Cs₂CO₃ (50 mmol) was added. A mesylate (prepared from3-diethylamino-1-propanol and methanesulfonyl chloride, GeneralProcedure P2) (30 mmol) was added to the reaction mixture and heated to90° C. until the reaction was complete as indicated by LC-MS (10 h).After cooling to rt, the reaction was quenched by cold H₂O (100 mL), andthe resulting mixture was extracted with EtOAc (3×100 mL). The combinedEtOAc extracts were washed with brine (3×50 mL) and dried (anhydrousNa₂SO₄). The solvent was removed in vacuo, and the crude product waspurified by silica gel column chromatography, eluting with 10% MeOH inDCM+0.5% Et₃N, giving the desired 4-(3-diethylaminopropoxy)benzaldehyde.

A solution of 2-t-butylamino-4-(4-n-butylphenoxy)aniline (synthesizedvia General Procedures G1 and G2 and H) (130 mg, 0.4 mmol) and4-(3-diethylaminopropoxy)benzaldehyde obtained above (70 mg, 0.3 mmol)in MeOH (10 mL) was subjected to General Procedure K. The solvent wasremoved in vacuo and the residue was purified by silica gel columnchromatography, eluting with 10% MeOH in DCM with a gradual increment ofEt₃N (0.5 to 1%), affording the desired benzimidazole (120 mg).

MS m/z 528 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ 0.84 (t, 3H), 1.05 (t, 6H), 1.24 (m, 2H),1.31 (s, 9H), 1.75 (m, 2H), 1.98 (m, 2H), 2.58 (q, 4H), 2.66 (t, 2H),4.09 (t, 2H), 4.13 (t, 2H), 6.93 (d, 2H,), 7.00 (dd, 1H), 7.02 (d, 2H),7.07 (d, 1H), 7.33 (d, 2H,), 7.62 (d, 2H), 7.72 (d, 1H) ppm.

Example 51-butyl-6-(4-tert-butyl-phenoxy)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole

To a stirred solution of 3-hydroxybenzaldehyde (20 mmol) in DMSO (50 mL)at rt, solid Cs₂CO₃ (60 mmol) was added. 1-(2-chloroethyl)pyrrolidinehydrochloride (30 mmol) was added to the reaction mixture and heated to90° C. for 9 h. After cooling to rt, the reaction was quenched by coldH₂O (50 mL), and the resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with brine (3×50 mL) anddried (anhydrous Na₂SO₄). The solvent was removed in vacuo to affordcrude 3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde.

A solution of 2-t-butylamino-4-(4-n-butylphenoxy)aniline (synthesizedvia General Procedures G1 and G2 and H) (130 mg, 0.4 mmol) and3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde obtained above (70 mg, ˜0.3mmol) in MeOH (10 mL) was subjected to General Procedure K. The solventwas removed in vacuo and the residue was purified by silica gel columnchromatography, eluting with 10% MeOH in DCM with a gradual increment ofEt₃N (0.5 to 1%), to afford the desired benzimidazole (100 mg).

MS m/z 512 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ0.83 (t, 3H), 1.22 (m, 2H), 1.29 (s, 9H), 1.74(m, 2H), 1.87 (m, 4H), 2.78 (m, 4H), 3.03 (m, 2H), 4.16 (t, 2H), 4.25(m, 2H), 6.94 (d, 2H), 7.01 (br d, 1H), 7.07 (m, 2H), 7.26 (m, 2H), 7.33(d, 2H), 7.41 (t, 1H), 7.74 (d, 1H) ppm.

The following Examples were synthesized according to the Methodsemployed for Examples 1-5;

Example Name 61-butyl-6-(4-tert-butyl-phenoxy)-2-[2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole 71-butyl-2-[3-(naphthalen-2-yloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 82-biphenyl-4-yl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 91-butyl-6-(4-tert-butyl-phenoxy)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole 101-butyl-2-[3-(3,3-dimethyl-butoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 111-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole 121-butyl-2-(3-phenoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 131-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H-benzimidazole 141-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H-benzimidazole 151-butyl-6-[2-(4-chloro-phenyl)-ethoxy]-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole 161-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H-benzimidazole 171-butyl-2-(4-tert-butyl-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 18dibutyl-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-phenyl}-amine 19(2-{3-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-ethyl)-diisopropyl-amine 20{3-[3-butyl-2-(4-tert-butyl-phenyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 211-butyl-2-(3,5-di-tert-butyl-2-methoxy-phenyl)-6-(2-piperazin-1-ylethoxy)-1H-benzoimidazole 22{3-[3-butyl-2-(3-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-propyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 231-butyl-2-naphthalen-2-yl-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole24 (2-{3-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-ethyl)-dimethyl-amine 252-benzofuran-2-yl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole26 1-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 272-benzhydryl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole 281-Butyl-2-(4-chloro-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 29{3-[3-Butyl-2-(4-isopropoxy-phenyl)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine 301-Butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(4,4,4-trifluoro-butoxy)-phenyl]-1H-benzoimidazole

Example 31(2-(3-butyl-2-(2,4,4-trimethylpentyl)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine

A solution of 2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline(synthesized via General Procedures G1 and G2 and H) (58.6 mg, 0.2 mmol)and 3,5,5-trimethylhexanal (31.2 mg, 0.22 mmol) in ethanol (2 mL) wassubjected to General Procedure K. The crude product was purified bysilica gel column chromatography using 10% MeOH in DCM with a gradualincrement of triethylamine (0.2 to 1.0%) as eluent to afford(2-(3-butyl-2-(2,4,4-trimethylpentyl)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine(41.0 mg).

MS m/z 416 (M+H)⁺

Example 321-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-3-yl-1H-benzimidazole

A solution of 1-(t-butyloxycarbonyl)piperidine-3-carboxaldehyde (235 mg;1.1 mmol) and2-[(5-pyrrolidin-1-yl)pentylamino]-4-(3-diethylaminopropoxy)-4-(2-diethylaminoethoxy)aniline(synthesized via General Procedures G1 and G2 and H) (362 mg; 1 mmol) inethanol (5 mL) was subjected to General Procedure K. The crude productwas purified by silica gel column chromatography using 10% MeOH in DCMwith a gradual increment of triethylamine (0.2 to 1.0%) as eluent toafford 410 mg of tert-butyl3-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate.

A solution of tert-butyl3-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate(271 mg; 0.5 mmol) in DCM (2 mL) was subjected to General Procedure T1.The resulting mixture was stirred for 4-5 h and the solvent was removedin vacuo. The residue obtained was washed with ether twice and driedunder vacuum to afford1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-3-yl-1H-benzimidazoletrihydrochloride (210 mg).

MS m/z 442 (M+H)⁺

Example 331-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-4-yl-1H-benzimidazole

A solution of 1-(t-butyloxycarbonyl)piperidine-4-carboxaldehyde (235 mg;1.1 mmol) and2-[(5-pyrrolidin-1-yl)pentylamino]-4-(3-diethylaminopropoxy)-4-(2-diethylaminoethoxy)aniline(362 mg; 1 mmol) in ethanol (5 mL) was subjected to General Procedure K.The crude product was purified by silica gel column chromatography using10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%)as eluent to afford 430 mg of tert-butyl4-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate.

A solution of tert-butyl4-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate(271 mg; 0.5 mmol) in DCM (2 mL) was subjected to General Procedure T1.The resulting mixture was stirred for 4-5 h and the solvent was removedin vacuo. The residue obtained was washed with ether twice and driedunder vacuum to afford1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-4-yl-1H-benzimidazoletrihydrochloride (220 mg).

MS m/z 442 (M+H)⁺

Example 34{1-butyl-[4,6-di(3-diethylaminopropoxy)]-2-piperidin-4-yl}-1H-benzimidazole

A solution of 1-(t-butyloxycarbonyl)piperidine-4-carboxaldehyde (235 mg;1.1 mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline(synthesized via General Procedures J1 and J2 and I) (424 mg; 1 mmol) inethanol (5 mL) was subjected to General Procedure K. The crude productwas purified by silica gel column chromatography using 10% MeOH in DCMwith a gradual increment of triethylamine (0.2 to 1.0%) as eluent toafford 425 mg of tert-butyl{4-[1-butyl-4,6-di(3-diethylaminopropoxy)-1H-benzimidazol-2-yl]}piperidine-1-carboxylate.

A solution of tert-butyl4-[1-butyl-4,6-di(3-diethylaminopropoxy)-1H-benzimidazol-2-yl]piperidine-1-carboxylate(308 mg; 0.5 mmol) in DCM (2 mL) was subjected to General Procedure T1.The resulting mixture was stirred for 4-5 h and the solvent was removedin vacuo. The residue obtained was washed with ether twice and driedunder vacuum to afford{1-butyl-[4,6-di(3-diethylaminopropoxy)]-2-piperidin-4-yl}-1H-benzimidazoletrihydrochloride (260 mg).

MS m/z 516 (M+H)⁺

Example 35(3-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine

Example 35 was formed employing 3-(4-t-butyl-phenoxy)benzaldehyde(synthesized via General Procedure B) (50 mg; 0.20 mmol) and2-butylamino-4-(3-diethylaminopropoxy)-6-(2-pyrrolidin-1-yl-ethoxy)aniline(synthesized via General Procedures J3-J7) (39 mg; 0.20 mmol) in ethanol(1 mL) according to General Procedure K. The crude product was purifiedby silica gel column chromatography using 10% MeOH in DCM with a gradualincrement of triethylamine (0.2 to 1.0%) as eluent to afford 40 mg ofExample 243.

MS m/z 641 (M+H)⁺

Example 361-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole

This compound was prepared according to the General Procedure K byrefluxing a mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde(synthesized via General Procedure A) (100 mg) andN²-Butyl-4-(2-pyrrolidin-1-ylethoxy)-benzene-1,2-diamine (synthesizedvia General Procedures G1 and G2 and H) (50 mg) in ethanol overnight.Ethanol was removed in vacuo and the residue was purified by silica gelchromatography using 5% MeOH in DCM to give pure1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole(37.0 mg, 40%).

MS: m/z 518 (M+H)⁺

Example 371-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

A mixture of 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine(synthesized via General Procedures G1 and G2 and H) (0.130 g, 0.512mmol) and 3-(3-tert-butylphenoxy)benzaldehyde was subjected to GeneralProcedure K. Reaction was concentrated and purified on silica gelchromatography using DCM-2% MeOH/DCM. The BOC-group was removedemploying General Procedure T1 to give1-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole(0.10 g).

MS (m/z): 527 (M+H)⁺

Example 381-butyl-2-{3-[biphenyl-4-yloxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

A mixture of 3-bromobenzaldehyde (1.05 g) and1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (1.85 g) wassubjected to General Procedure K. The ethanol was removed in vacuo andthe residue purified on silica gel using 1-2% MeOH/DCM.

To a solution of the aryl bromide (0.07 mmol) in pyridine (1 mL) wasadded copper powder (0.14 mmol) followed by K₂CO₃ (0.35 mmol) and therespective substituted phenol (0.14 mmol). The mixture was heated at110° C. overnight, then diluted with water (2 mL) and extracted withEtOAc (3×2 mL). The combined organic extract was dried over Na₂SO₄,filtered and concentrated to an oil, which was purified by columnchromatography on silica gel. The pure product was obtained from 1-6%methanol/DCM (yield 28-42%). The BOC-group was removed via GeneralProcedure T1 to give1-butyl-2-{3-[biphenyl-4-yloxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole.

MS (m/z): 547 (M+H)⁺

Example 391-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

A mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-benzaldehyde (0.08 g) and1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (0.10 g) wassubjected to General Procedure K. Ethanol was removed in vacuo and theresidue purified on silica gel with 1-2% MeOH/DCM. The BOC-group wasremoved employing General Procedure T1 to give1-butyl-2-{(4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole(0.081 g).

MS (m/z): 533 (M+H)⁺

The following Examples were synthesized according to the Methodsemployed for Examples 35-39;

Example Name 40[3-(3-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-4-nitro-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 41[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-ethyl]-diethyl-amine 421-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(piperidin-4-ylmethoxy)-1H-benzoimidazole 431-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 44{3-[3-butyl-2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 451-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole 461-butyl-6-[2-(4-butyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 47{3-[3-butyl-2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 48(3-{3-butyl-2-[3-(4-methoxy-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 49{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino-ethoxy)-benzimidazol-1-yl]-propyl}-diethyl-amine 50[3-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-benzimidazol-4-yloxy)-propyl]-diethyl-amine 51[3-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-benzimidazol-5-yl)-propyl]-diethyl-amine 521-butyl-2-[3-(2-isopropyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 53{3-[3-butyl-2-(2-{4-[3-(4-methoxy-phenyl)-propoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 54{3-[3-butyl-2-(2-{4-[4-(4-methoxy-phenyl)-butoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 55[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-3-ethoxy-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 56(3-{3-butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 571-butyl-2-[3-(4-chloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 581-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 591-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(piperidin-4-yloxy)-1H-benzoimidazole 603-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzoimidazol-5-yloxy)-1-aza-bicyclo[2.2.2]octane 611-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2,2,6,6,-tetramethyl-piperidin-4-yioxy)-1H-benzoimidazole 622-[3-(4-butoxy-phenoxy)-phenyl]-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 63[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 64{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-(3-methyl-butyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 65[3-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-hexyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 66{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino-ethoxy)-benzimidazol-1-yl]-propyl}-dimethyl-amine 671-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2-piperazin-1-ylethoxy)-1H-benzoimidazole 68[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 69{3-[2-(4-benzyloxy-3,5-dimethyl-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 70{3-[3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 711-butyl-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 721-butyl-6-[2-(4-isopropyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole 731-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-piperazin-1-yl-propoxy)-1H-benzoimidazole 74(3-{3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 751-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperidin-4-yloxy)-1H-benzoimidazole 761-butyl-2-[3-(4-chloro-benzyloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 771-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 78(3-{2-[2-(4-benzyloxy-phenyl)-ethyl]-3-butyl-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 79(3-{3-butyl-2-[2-(4-phenethyloxy-phenyl)-ethyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 80{3-[3-butyl-2-(2-{4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 81[3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)-phenyl]-ethyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 82(3-{3-butyl-2-[4-(4-fluoro-benzyloxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 83{3-[2-(3-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 84[3-(3-butyl-2-{4-chloro-3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 851-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole 861-butyl-2-[4-(4-isopropyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 871-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-1H-benzoimidazole 881-butyl-6-[2-(4-butyl-piperazin-1-yl)-ethoxy]-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-benzoimidazole 891-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 901-butyl-2-[4-(4-tert-butyl-benzyl)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 91N-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2,2-dimethyl-propioinamide 92(3-{3-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 931-butyl-2-[4-(naphthalen-2-yloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 941-butyl-2-[3-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 95[3-(3-butyl-2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 964-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2-(4-chloro-phenyl)-ethoxy]-phenylamine 971-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-isopropyl-urea 98{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-dimethylamino-ethoxy)-benzimidazol-1-yl]-propyl}-dimethyl-amine 991-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H-benzimidazole 1001-butyl-6-(4-cyclopentyl-phenoxy)-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-benzoimidazole 101{3-[2-(4-benzyloxy-phenyl)-3-cyclopentylmethyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 1021-butyl-6-(4-butyl-phenoxy)-2-{3,5-dimethyl-4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1H-benzoimidazole 1031-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-pyrrolidin-1-yl-propoxy)-1H-benzoimidazole 104{3-[2-(4-benzyloxy-phenyl)-3-isobutyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 105[3-(3-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 1061-butyl-6-(1-butyl-piperidin-4-yloxy)-2-[3-(3,5-dichloro-phenoxy)-phenyl]-1H-benzoimidazole 1071-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(1-ethyl-piperidin-4-yloxy)-1H-benzoimidazole 1081-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-benzoimidazole 109diethyl-{3-[3-isobutyl-2-(2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yloxy]-propyl}-amine 110{3-[2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3-isobutyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 1111-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 1121-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 1131-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H-benzimidazole 114{3-[2-(4-benzyloxy-phenyl)-3-cyclopentyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 1151-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-5-(4-methyl-piperazin-1-ylmethyl)-1H-benzoimidazole 116[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-ethyl]-dimethyl-amine 117[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzimidazol-5-yloxy)-ethyl]-diisopropyl-amine 1181-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1H-benzimidazole 119(3-{1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 1202-(3-butoxy-phenyl)-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole 1211-butyl-2-[3-(4-methanesulfonyl-benzyloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 1224′{3-[1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-phenoxy}-biphenyl-4-carbonitrile 123{3-[2-(4-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 1241-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 1251-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[2-(4-isopropyl-piperazin-1-yl)-ethoxy]-1H-benzoimidazole 126{3-[2-(3-benzyloxy-4-methoxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 127(3-{3-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 128{3-[3-butyl-2-(3-phenoxy-phenyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 1291-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-1H-benzimidazole 1301-butyl-2-[4-(2,3-di-methoxy-phenoxy)-phenyl]-6-(2-piperazin-1-ylethoxy)-1H-benzoimidazole 131[3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)-phenyl]-ethyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 132(3-{3-butyl-2-[3-(4-chloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 133{3-[2-(4-benzyloxy-phenyl)-3-isopropyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 134(2-{3-butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-ethyl)-diisopropyl-amine 1351-butyl-6-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 136{3-[3-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 137(3-{2-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-ethyl)-cyclohexyl-methyl-amine 1381-butyl-6-[2-(4-propyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 1391-butyl-6-(4-butyl-phenoxy)-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-benzoimidazole 1401-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-morpholin-4-yl-ethoxy)-1H-benzimidazole 1414-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-phenethyloxy-phenylamine 142{2-[2-(4-benzyloxy-phenyl)-3-phenethyl-3H-benzimidazol-5-yloxy]-ethyl}-diethyl-amine 143{3-[3-butyl-2-(4-phenoxy-phenyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 1443-[4-(2-{3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-ethyl)-piperazin-1-yl]-propan-1-ol 1451-butyl-6-(2-pyrrolidin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 146{2-[2-[4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino-ethoxy)-benzimidazol-1-yl]-ethyl}-dimethyl-amine 1471-butyl-6-(2-morpholin-4-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole 1481-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(1-methyl-piperidin-4-yloxy)-1H-benzoimidazole 149N′-[3-butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzimidazol-5-yl]-N,N-diethyl-propane-1,3-diamine 1501-butyl-2-[3-(2,4-dichloro-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 1511-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-morpholin-4-yl-ethoxy)-1H-benzimidazole 1521-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[4-(4-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole 1532-[4-(biphenyl-4-yloxy)-phenyl]-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 1541-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-morpholin-4-yl-ethoxy)-1H-benzimidazole 1551-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 1561-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-5-(1H-imidazol-4-ylmethoxy)-1H-benzoimidazole 157{3-[2-(2-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 158{3-[1-Butyl-6-(3-diethylamino-propoxy)-2-piperidin-4-yl-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 159(2-{2-[2-(4-Benzyloxy-phenyl)-ethyl]-3-phenethyl-3H-benzoimidazol-5-yloxy}-ethyl)-diethyl-amine 160[3-(3-Butyl-2-{3-[4-(4-fluoro-benzyloxy)-phenyl]-propyl}-3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine 161[3-(4-Benzyloxy-phenyl)-propyl]-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-amine 162{3-[3-Butyl-2-(3-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-propyl)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine 1631-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-imidazol-1-yl-ethoxy)-1H-benzoimidazole 1641-[4-(2-{3-Butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-ethyl)-piperazin-1-yl]-ethanone 165N-[3-Butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-3H-benzoimidazol-5-yl]-N-(3-diethylamino-propyl)-N′,N′-diethyl-propane-1,3-diamine

Example 166(3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine

This compound was prepared according to General Procedure K by refluxinga mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (300 mg) andN¹-Butyl-3,5-bis-(3-diethylamino-propoxy)-benzene-1,2-diamine(synthesized via General Procedures J1 and J2 and I) (200 mg) in ethanolovernight. Ethanol was removed in vacuo and the residue was purified bysilica gel chromatography using 5% MeOH in DCM to give pure(3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine(100 mg).

MS: m/z 663 (M+H)⁺

Example 167{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]propyl}diethyl-amine

{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-aminewas formed employing 3(4-t-butyl-phenoxy)benzaldehyde (127 mg; 0.50mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesizedvia General Procedures J1 and J2 and I) (1.6 mg; 0.25 mmol) in ethanol(1 mL) following General Procedure K. The crude product was purified bysilica gel column chromatography using 10% MeOH in DCM with a gradualincrement of triethylamine (0.2 to 1.0%) as eluent to afford 145 mg(76%) of{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine.

MS: m/z 657 (M+H)⁺

Example 168{3-[2-(2-[4-[2-(4-chloro-phenyl)-ethoxy])-phenyl]-ethyl)-6-(3-diethylaminopropoxy)-3H-benzimidazole-4-yloxy]-propyl}diethyl-amine

This compound was prepared according to the General Procedure K byrefluxing a mixture of 3-{4-[2-(4-chloro-phenyl)-ethoxy]-propionaldehyde(100 mg) and 3,5-Bis-(3-diethylamino-propxy)-benzene-1,2-diamine(synthesized via General Procedures J1 and J2 and I) (50 mg) in ethanolovernight. Ethanol was removed in vacuo and the residue was purified bysilica gel chromatography using 10% MeOH in DCM to give{3-[2-(2-[4-[2-(4-chloro-phenyl)-ethoxy])-phenyl]-ethyl)-6-(3-diethylaminopropoxy)-3H-benzimidazole-4-yloxy]-propyl}diethyl-amine(30 mg).

MS: m/z 635 (M+H)⁺

Example 169(3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine

4-(4-Chloro-3-trifluoromethyl)phenoxybenzaldehyde (synthesized employingGeneral Procedure B) (150 mg) and2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized viaGeneral Procedures J1 and J2 and I) 106 mg; 0.25 mmol) in ethanol (1 mL)were condensed employing General Procedure K. The crude product waspurified by silica gel column chromatography using 10% MeOH in DCM witha gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford160 mg of(3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine.

MS: m/z 703 (M+H)⁺

Example 170(3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine

A solution of 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline(synthesized via General Procedures J1 and J2 and I) (84.4 mg, 0.2 mmol)and 4-(4-fluoro-3-trifluoromethyl)phenoxybenzaldehyde (synthesizedemploying General Procedure B) (62.5 mg, 0.2 mmol) in ethanol (2 mL) washeated to reflux following the General Procedure K. The crude productwas purified by silica gel column chromatography using 10% MeOH in DCMwith a gradual increment of triethylamine (0.2 to 1.0%) as eluent toafford3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine(62 mg).

MS m/z 687 (M+H)

The following Examples were synthesized according to the Methodsemployed for Examples 166-170;

Example Name 171{3-[2-[3-(3,5-Dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 1721-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 173{3-[2-[3-(3,4-Dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 174(3-{6-(3-diethylamino-propoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 175{3-[1-Butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 176{3-[2-[3-(4-Chloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 177{3-[1-Butyl-2-[3-(4-chloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 178{3-[1-Butyl-6-(3-diethylamino-propoxy)-2-(3-p-tolyloxy-phenyl)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 179{3-[1-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 1801-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 181{3-[3-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine 182(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(3-fluoro-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 183{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-diethylamino-propoxy)-1-isopropyl-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 184{3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 1852-{4-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl-phenoxy}-benzoic acid methyl ester 186{3-[2-[4-(biphenyl-4-yloxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 187{3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 188{3-[1-butyl-2-[4-(4-chloro-benzylsulfanyl)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 189{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-diethylamino-propoxy)-3H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 190(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 191[3-(1-butyl-6-(3-diethylamino-propoxy)-2-{4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 192(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 193{3-[2-[3-(4-tert-Butyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 194(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-trifluoromethyl-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 195{3-[1-Butyl-2-[4-chloro-2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 1962-[3-(4-Chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 1971-Butyl-2-[3-(4-chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 198{3-[3-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine199{2-[1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-diisopropylamino-ethoxy)-1H-benzimidazol-4-yloxy]-ethyl}-diethyl-amine 200{3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine201 {3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine202 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-methoxy-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 2031-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 2042-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 2051-Butyl-2-[4-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 2061-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 207{3-[1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 2082-[5,7-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenol 2092-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzimidazole 210(3-{6-(3-Diethylamino-propoxy)-2-[2-(1,1-difluoro-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 211{3-[1-Butyl-2-[4-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 2122-[4-(4-tert-Butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 213{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 214[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-diethylaminomethyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 215(3-{6-(3-Diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 216(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 217{3-[6-(3-Diethylamino-propoxy)-2-(3-p-tolyloxy-phenyl)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 2184-{3-[1-Butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-phenoxy}-benzonitrile 219[3-(3-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-pyrrolidin-1-yl-3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine 220{3-[1-butyl-2-[4-(4-chloro-phenylmethanesulfinyl)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl- amine221 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(naphthalen-2-yloxy)-phenyl]-1H-benzoimidazole-4-yloxy}-propyl)-diethyl-amine 222(3-{6-(3-diethylamino-propoxy)-2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 223(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[3-(4-methoxy-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 2242-[3-(3,4-Dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 225{3-[2-[4-(4-tert-Butyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 226{3-[3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-[2-(tetrahydro-furan-2-yl)-ethoxy]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 2271-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 228[3-(7-Butoxy-3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine 2294-{3-[4,6-Bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-phenoxy}-benzonitrile 2302-[3-(3,5-Dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 231{3-[1-butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl- amine232 {3-[1-butyl-6-(3-diethylamino-propoxy)-2-(3-phenoxy-phenyl)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 233{3-[1-Butyl-2-[2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine234 2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 235{3-[1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine236 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-methyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 237{3-[1-butyl-6-(3-diethylamino-propoxy)-2-(4-phenoxy-phenyl)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 2385-[4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-2-[2-(4-chloro-phenyl)-ethoxy]-phenol 239[3-(6-Butoxy-1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-benzoimidazol-4-yloxy)-propyl]-diethyl-amine 240{3-[2-[4-Chloro-2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine241 1-butyl-4-(4-chloro-benzyloxy)-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 2424-{4-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-phenoxy}-benzonitrile 243[3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-fluoro-1H-benzoimidazol-4-yloxy)-propyl]-diethyl-amine 244(3-{6-(3-diethylamino-propoxy)-2-[3-(4-methoxy-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 245(3-{6-(3-diethylamino-propoxy)-2-[4-(4-methoxy-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 246{3-[1-butyl-2-[4-(4-chloro-3-fluoro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yl]-propyl}-diethyl-amine 247(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(quinolin-8-yloxy)-phenyl]-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 248{3-[2-[2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine249 2-[{2-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-ethyl}-(2-chloro-ethyl)-amino]-ethanol 250(3-{6-(3-Diethylamino-propoxy)-2-[3-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 251[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-isopropoxy-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 252[3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-cyclopentylmethoxy-1H-benzoimidazol-4-yloxy)-propyl]-diethyl-amine 2531-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazole 254{3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-3-(3-diethylamino-propoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine

Example 255{3-[2-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl}-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 2,4-dihydroxybenzaldehyde (10 mmol) in DMSO (50mL) at rt, solid Cs₂CO₃ (45 mmol) was added. A mesylate (prepared from3-diethylamino-1-propanol and methanesulfonyl chloride, GeneralProcedure P2) (25 mmol) was added to the reaction mixture and heated to90° C. until the reaction was complete as indicated by LC-MS (˜10 h).After cooling to rt, the reaction was quenched by cold H₂O (100 mL), andthe resulting mixture was extracted with EtOAc (3×100 mL). The combinedEtOAc extracts were washed with brine (3×50 mL) and dried (anhydrousNa₂SO₄). The solvent was removed in vacuo to afford the desired2,4-bis(3-diethylaminopropoxy)benzaldehyde which was used for furthertransformation.

To a stirred solution of 2,4-difluoronitrobenzene (50 mmol), Et₃N (100mmol) and DMF (80 mL) was added dropwise a solution of n-butylamine (51mmol) in DMF (20 mL) at rt, and the mixture was stirred at rt for 5 h.The reaction was quenched by cold H₂O (100 mL), and the resultingmixture was extracted with EtOAc (4×100 mL). The combined EtOAc extractswere washed with brine (3×60 mL) and dried (anhydrous Na₂SO₄). Thesolvent was removed in vacuo to afford the desired2-n-butylamino-4-fluoronitrobenzene which was used for furthertransformation.

A mixture of 2-n-butylamino-4-fluoronitrobenzene (10 mmol),4-t-butylphenol (13 mmol), solid K₂CO₃ (30 mmol) and DMF (30 mL) washeated with stirring at 90° C. for 10 h. The reaction was quenched bycold H₂O (50 mL), and the resulting mixture was extracted with EtOAc(3×100 mL). The combined EtOAc extracts were washed with brine (2×50 mL)and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo, and thecrude products were purified by silica gel column chromatography(eluting with 10% EtOAc in hexane), giving2-n-butylamino-4-(4-t-butylphenoxy)nitrobenzene.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by LC-MS (˜4 h). The reaction mixture was thenfiltered through a celite pad to remove the catalyst. The MeOH solutioncontaining 2-n-butylamino-4-(4-butylphenoxy)aniline was used directlyfor further transformation.

A solution of 2-n-butylamino-4-(4-t-butylphenoxy)aniline (130 mg, 0.4mmol) and 2,4-bis(3-diethylaminopropoxy)benzaldehyde obtained above (110mg, 0.3 mmol) in MeOH (10 mL) was refluxed until the reaction wascomplete. The solvent was removed in vacuo and the residue was purifiedby silica gel column chromatography, eluting with 10% MeOH in DCM with agradual increment of Et₃N (0.5 to 1%), to afford the desiredbenzimidazole (100 mg).

MS m/z 657 (M+H)⁺

¹H NMR (400 MHz, CDCl₃) of HCl salt of the benzimidazole: δ 0.80 (t,3H), 1.19 (m, 2H), 1.26 (t, 6H), 1.32 (s, 9H), 1.41 (t, 6H), 1.74 (m,2H), 2.44 (m, 4H), 3.12-3.39 (m, 12H), 4.21 (t, 2H), 4.29 (m, 4H), 6.68(br d, 1H), 6.79 (br s, 1H), 6.98 (d, 2H), 7.17 (d, 1H), 7.22 (dd, 1H),7.35 (d, 1H), 7.40 (d, 2H), 8.06 (d, 1H), 11.4 (br, N.HCl), 11.9 (br,N.HCl) ppm.

Example 256(3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine

A solution of2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde(synthesized via General Procedures D1 and D2) (429 mg; 1.1 mmol) and2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline (synthesized viaGeneral Procedures G1 and G2 and I) (293 mg; 1 mmol) in ethanol (5 mL)was heated to reflux following General Procedure K. The crude productwas purified by silica gel column chromatography using 10% MeOH in DCMwith a gradual increment of triethylamine (0.2 to 1.0%) as eluent toafford of(3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine(430 mg).

MS m/z 663 (M+H)⁺

Example 257(3-{1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-(3-diethylamino-propoxy)-phenyl]-1H-benzimidazol-4-yloxy}propyl)-diethyl-amine

To a stirred solution of 4-hydroxybenzaldehyde (20 mmol) in DMSO (80 mL)at rt, solid Cs₂CO₃ (50 mmol) was added. The mesylate prepared from3-diethylamino-1-propanol and methanesulfonyl chloride, GeneralProcedure P2 (30 mmol) was added to the reaction mixture and heated to90° C. until the reaction was complete. After cooling to rt, thereaction was quenched by cold H₂O (100 mL), and the resulting mixturewas extracted with EtOAc (3×100 mL). The combined EtOAc extracts werewashed with brine (3×50 mL) and dried (anhydrous Na₂SO₄). The solventwas removed in vacuo, and the crude product was purified by silica gelcolumn chromatography (eluting with 10% MeOH in DCM+0.5% Et₃N) to afford4-(3-diethylaminopropoxy)benzaldehyde.

To a stirred solution of6-(3-diethylaminopropoxy)-2,4-difluoronitrobenzene (11 mmol) andtriethylamine (22 mmol) in DMF (20 mL), a solution of n-butylamine (11mmol) in DMF (8 mL) was added dropwise at rt, and the mixture wasstirred at rt for 10 h. The reaction was quenched by cold H₂O (50 mL),and the resulting mixture was extracted with EtOAc (3×100 mL). Thecombined EtOAc extracts were washed with brine (3×50 mL) and dried(anhydrous Na₂SO₄). The solvent was removed in vacuo to afford thedesired 2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzenewhich was used for further transformation.

A mixture of2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene obtainedabove (3 mmol), 4-t-butylphenol (4 mmol), solid K₂CO₃ (9 mmol) and DMF(15 mL) was heated with stirring at 90° C. for 15 h. The reaction wasquenched by cold H₂O (30 mL), and the resulting mixture was extractedwith EtOAc (3×100 mL). The combined EtOAc extracts were washed withbrine (2×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed invacuo, and the crude products were purified by silica gel columnchromatography (eluting with 10% MeOH in DCM), giving2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)nitrobenzene.

The nitro intermediate (1 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (40 mg) untilcompletion as indicated by LC-MS (˜4 h). The reaction mixture was thenfiltered to remove the catalyst. The MeOH solution containing2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)aniline wasused directly for further transformation.

A solution of2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)-aniline(90 mg, 0.2 mmol) and 4-(3-diethylaminopropoxy)benzaldehyde obtainedabove (65 mg, 0.25 mmol) in MeOH (10 mL) was refluxed until the reactionwas complete as indicated by LC-MS (˜10 h). The solvent was removed invacuo and the residue was purified by silica gel column chromatography,eluting with 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to1%), to afford the desired benzimidazole (80 mg).

MS m/z 657 (M+H)⁺

¹H NMR (400 MHz, CDCl₃) of HCl salt of the benzimidazole: δ 0.80 (t,3H), 1.21 (m, 2H), 1.31 (s, 9H), 1.40 (m, 12H), 1.74 (m, 2H), 2.39 (m,2H), 2.52 (m, 2H), 3.17-3.27 (m, 12H), 3.80 (m, 2H), 4.18 (m, 4H), 6.60(br s, 1H), 6.62 (br s, 1H), 6.95 (d, 2H), 7.14 (br, 2H), 7.39 (d, 1H),7.80 (br, 2H), 11.17 (br, N.HCl), 11.83 (br, N.HCl) ppm.

Example 2582-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazole

A solution of 2-n-butylamino-4-(4-t-butylphenoxy)aniline (synthesizedvia General Procedures J3-J7) (100 mg, 0.3 mmol) and2,4-bis[2-(1-methyl-2-pyrrolidin-2-yl)-ethoxy]benzaldehyde (synthesizedvia General Procedure C) (55 mg, 0.15 mmol) in MeOH (10 mL) wassubjected to General Procedure K. The solvent was removed in vacuo andthe residue was purified by silica gel column chromatography, elutingwith 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to 1%), toafford the desired benzimidazole (50 mg).

MS m/z 653 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ 0.73 (t, 3H), 1.10-2.53 (m, 22H), 1.32 (s,9H), 2.20 (s, 3H), 2.39 (s, 3H), 3.94-3.99 (m, 6H), 6.50 (m, 2H), 6.92(d, 2H), 6.98 (m, 1H), 7.05 (d, 1H), 7.32 (d, 2H), 7.42 (d, 1H), 7.70(d, 1H) ppm.

Example 2592-[2,4-bis-(2-pyrrolidin-1-yl)-ethoxy]-phenyl}-1-butyl-6-(4-butyl-phenoxy)-1H-benzimidazole

A solution of 2-n-butylamino-4-(4-n-butylphenoxy)aniline (synthesizedvia General Procedures G1 and G2 and I) (80 mg, 0.25 mmol) and2,4-bis(2-pyrrolidin-1-yl-ethoxy)benzaldehyde (synthesized via GeneralProcedure C) (50 mg, 0.15 mmol) was subjected to General procedure K.The solvent was removed in vacuo and the residue was purified by silicagel column chromatography, eluting with 10% MeOH in DCM with a gradualincrement of Et₃N (0.5 to 1%), to afford the desired benzimidazole (80mg).

MS m/z 625 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ0.73 (t, 3H), 0.92 (t, 3H), 1.10 (m, 2H), 1.35(m, 2H), 1.55-1.60 (m, 4H), 1.64 (m, 4H), 1.83 (m, 4H), 2.39 (m, 4H),2.58 (t, 2H), 2.65 (m, 4H), 2.73 (t, 2H), 2.93 (t, 2H), 3.96 (t, 2H),4.07 (t, 2H), 4.16 (t, 2H), 6.60 (br s, 1H), 6.62 (dd, 1H), 6.92 (d,2H), 6.96 (dd, 1H), 7.04 (d, 1H), 7.12 (d, 2H), 7.40 (d, 1H), 7.70 (d,1H) ppm.

The following Examples were synthesized according to the Methodsemployed for Examples 255-259;

Example Name 2601-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolodin-1-yl-ethoxy)-phenyl]-6-(2-pyrrolodin-1-yl-ethoxy)-1H-benzoimidazole 261{3-[2-{1-butyl-6-[2-(4-chloro-phenyl)-ethoxy]-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 2622-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-butyl-phenoxy)-1H-benzoimidazole 263{3-[2-[1-butyl-5-(4-tert-butyl-phenoxy)-1H-benzimidazol-1-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 2641-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 2652-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-cyclopentyl-phenoxy)-1H-benzoimidazole 2662-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-cyclopentyl-phenoxy)-1H-benzoimidazole 267{3-[2-[1-butyl-6-(4-iospropyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 268(2-{1-butyl-6-(2-dimethylamino-ethylsulfanyl)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine 2692-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazole 270{3-[2-[1-butyl-6-(4-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 271{3-[2-[1-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 2722-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-isopropyl-phenoxy)-1H-benzoimidazole 2731-Butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 274(3-{3-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 275{3-[2-[1-butyl-6-(4-cyclopentyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 276{3-[2-[1-butyl-4-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 2772-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-isopropyl-phenoxy)-1H-benzoimidazole 278(3-{5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1-isopropyl-1H-benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine 2791-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 2801-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(1-methyl-piperidin-4-yloxy)-1H-benzimidazole 281{3-[2-[6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 2821-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolidin-2-ylmethoxy)-1H-benzoimidazole 283(3-{3-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-diethylamino-ethoxy)-phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 284(3-{2-[1-Butyl-6-(2-imidazol-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 285(3-{2-[1-Butyl-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 286{3-[2-(3,5-bis-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 2874,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-1H-benzoimidazole 2881-butyl-2-[3-(4-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 2891-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolidin-2-ylmethoxy)-1H-benzoimidazole 290(2-{1-butyl-6-(2-dimethylamino-ethylsulfanyl)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole-4-ylsufanyl}-ethyl)-dimethyl-amine291 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-isopropyl-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 2924,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(3,5-dichlorophenoxy)-phenyl]-1H-benzoimidazole 2931-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-[2-(cyclohexyl-methyl-amino)-ethoxy]-1H-benzoimidazole 294{3-[1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-imidazol-1-yl-ethoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 295[3-(2-{3,4-bis-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-butyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 2961-butyl-4,6-bis-(1-methyl-piperidin-4-yloxy)-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole 2974,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole 2981-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidin-2-ylmethoxy)-1H-benzoimidazole 299[3-(2-{2-benzyloxy-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 300{3-[2-[1-Butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 301{3-[2-[1-Butyl-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 3021-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 303(2-{1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-dimethylamino-ethylsulfanyl)-1H-benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine 3041-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidin-3-yloxy)-1H-benzoimidazole 305{3-[2-[3-(3,4-bis-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 306(3-{5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine 3071-butyl-2-[4-(2-diethylamino-ethoxy)-phenyl]-4,6-bis-[2-(methyl-phenyl-amino)-ethoxy]-1H-benzimidazole 308{3-[3-butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-7-(pyridin-3-yloxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 309{2-[1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-diisopropylamino-ethoxy)-1H-benzimidazol-4-yloxy]-ethyl}-diethyl-amine 310{3-[3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-(pyridin-3-ylmethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 3112-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenol 312{3-[3-butyl-2-[2-(4-chloro-phenylsulfanyl)-phenyl]-7-(3-diethylamino-propoxy)-3H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 313(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-2-methoxy-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 314[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-isopropoxy-phenyl}-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 315{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-acetic acid methyl ester 316(3-{2-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 317(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(2-isopropoxy-phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 318(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(2,3-dimethoxy-phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 319(3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 320(2-{1-butyl-6-fluoro-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole-4-ylsufanyl}-ethyl)-dimethyl-amine 321 Methanesulfonicacid 5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-phenyl ester 3225-[2-(4-Chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-phenol 323{3-[1-butyl-6-(3-diethylamino-propoxy)-2-(4-pyrrolidin-1-yl-phenyl)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 3241-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-methyl-piperidin-4-yloxy)-1H-benzimidazole 3251-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-4,6-bis-(2-imidazol-1-yl-ethoxy)-1H-benzoimidazole 326[2-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-fluoro-1H-benzoimidazol-4-ylsulfanyl)-ethyl]-dimethyl-amine

Example 327{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-(pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine

4-[2-(4-chloro-phenyl)-ethoxy]-[2-(2-pyrrolidin-1-yl-ethoxy]-benzaldehyde(synthesized via General Procedures D1 and D2) (0.030 g, 0.080 mM) andN-butyl-3,5-bis(3-dimethylamino-propoxy)benzene-1,2-diamine (0.035 g,0.080 mM) were subjected to General Procedure K. After removal ofethanol, the residue was purified on silica gel using 10% MeOH/DCM with0.1-0.4% Et₃N, yield 0.025 g.

LC/MS (m/z): 776 (M+H)⁺

Example 3281-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole

A solution of 2-butylamino-4,6-bis(2-pyrrolidinyl-1-ethoxy)aniline(synthesized via General Procedures G1 and G2 and H) (78.4 mg, 0.2 mmol)and2-pyrrolidin-1-yl-ethoxy-4-(4-fluoro-3-trifluoromethyl)phenoxybenzaldehyde(synthesized via General Procedure E) (91 mg, 0.22 mmol) was subjectedto General Procedure K. The crude product was purified by silica gelcolumn chromatography using 10% MeOH in DCM with a gradual increment oftriethylamine (0.2 to 1.0%) as eluent to afford Example 328 (62 mg).

MS m/z 768 (M+H)⁺.

Example 3291-Butyl-2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-

4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole

A solution of 2-butylamino-4,6-bis(2-pyrrolidinyl-1-ethoxy)aniline(synthesized via General Procedures G1 and G2 and H) (78.4 mg, 0.2 mmol)and2-pyrrolidin-1-yl-ethoxy-4-(4-chloro-3-trifluoromethyl)phenoxybenzaldehyde(synthesized via General Procedure E) (91 mg, 0.22 mmol) in ethanol (2mL) was subjected to General Procedure K. The crude product was purifiedby silica gel column chromatography using 10% MeOH in DCM with a gradualincrement of triethylamine (0.2 to 1.0%) as eluent to afford Example 329(62.5 mg)

MS m/z 784 (M+H)⁺

Example 330(3-{2-[1-butyl-6-(3-diethylamino-propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine

A solution of2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde(synthesized via General Procedure E) (858; 2.2 mmol) and2-(n-butylamino)-4-(N,N-diethylaminopropoxy)-6-(N-pyrrolidinoethoxy)aniline(synthesized via General Procedures J3-J7) (816 mg; 2 mmol) in ethanol(5 mL) was subjected to General Procedure K. The crude product waspurified by silica gel column chromatography using 10% MeOH in DCM witha gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford520 mg (34%) of Example 330.

MS m/z 776 (M+H)⁺

Example 331(3-{2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]phenoxy}-propyl)-diethyl-amine

To a stirred solution of 2-(4-chlorophenyl)ethanol (20.0 mL, 148 mmol),TEA (31.0 mL, 222 mmol) in anhydrous DCM (100 mL) was added dropwiseMsCl (12.0 mL, 156 mmol) at 0° C. within 8 min, and stirred at the sametemperature for 2 h. The resulting yellow suspension was diluted withDCM (200 mL), washed with cold H₂O and brine, and dried. Removal of thesolvent afforded the mesylate (33.0 g).

A mixture of the mesylate obtained as above (23.6 g, 100 mmol),2,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and KHCO₃ (12.0 g, 120mmol) in anhydrous DMF (150 mL) was heated at 130° C. for 4 h followingthe general procedure described for disubstituted benzaldehydes. Thecrude products were purified by flash chromatography (eluting with 10%EtOAc in hexanes), giving 4-(4-chlorophenyl)ethoxysalicylaldehyde (12.5g) as a white solid.

Methanesulfonyl chloride, General Procedure P2 (2.90 mL, 37.5 mmol) wasadded dropwise at 0° C. to a stirred solution of 3-diethylaminopropanol(5.75 mL, 38.8 mmol), TEA (7.0 mL, 50.0 mmol) in anhydrous DCM (25 mL),and the mixture was stirred at the same temperature for 1 h, and at rtfor an additional 1 h. After the removal of the solvent in vacuo, thesolid residue was mixed with the aldehyde formed above (7.0 g, 25.0mmol), Cs₂CO₃ (20.4 g, 62.5 mmol) and anhydrous DMSO (100 mL), and thewhole mixture was heated at 90° C. for 6 h. following the generalprocedure described for disubstituted benzaldehydes to obtain oily2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (11.0g, ˜100% yield), which solidified upon standing.

To a stirred solution of 2,4,6-trifluoronitrobenzene (5.31 g, 30 mmol),TEA (8.37 mL, 60 mmol) and DMF (50 mL) was added dropwise a solution ofn-butylamine (2.96 mL, 30 mmol) in DMF (20 mL) at rt following GeneralProcedure G1 to obtain crude 2-butylamino-4,6-difluoronitrobenzene (9.0g). This product was mixed with 3-diethylaminopropanol (11.1 mL, 75mmol) and anhydrous THF (150 mL), and then powdered KOBu^(t) (8.5 g, 75mmol) was added following General Procedure G2 to afford crude2-butylamino-4,6-di(3-diethylaminopropoxy)nitrobenzene (15.5 g).

The nitro compound formed above (6.8 g, 15 mmol) dissolved in MeOH (90mL) was hydrogenated following general procedure H and2-butylamino-4,6-di(3-diethylaminopropoxy)aniline obtained was useddirectly for the next step.

Example 331 was formed employing phenylenediamine formed above (848 mg;2 mmol) and2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (858;2.2 mmol) in ethanol (5 mL) following the general procedure K. The crudeproduct was purified by silica gel column chromatography using 10% MeOHin DCM with a gradual increment of triethylamine (0.2 to 1.0%) to afford400 mg of Example 331.

MS m/z 792 (M+H)⁺

Example 332(3-{2-[1-Butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine

2-butylamino-4,6-difluoronitrobenzene (9.0 g) was mixed with1-pyrrolidineethanol (8.81 mL, 75 mmol) and anhydrous THF (150 mL), andthen powdered KOBu^(t) (8.5 g, 75 mmol) was added following generalprocedures G1 and G2 described for homo disubstituted phenylenediamineto afford crude 2-butylamino-4,6-di(pyrrolidineethoxy)nitrobenzene (13.5g).

The nitro compound formed above (6.3 g, 15 mmol) dissolved in MeOH (90mL) was hydrogenated following general procedure H and2-butylamino-4,6-di(pyrrolidineethoxy)aniline obtained was used directlyfor the next step.

Example 332 was formed employing phenylenediamine formed above (784 mg;2 mmol) and2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (858;2.2 mmol) in ethanol (5 mL) following the general procedure K. The crudeproduct was purified by silica gel column chromatography using 10% MeOHin DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluentto afford 380 mg of Example 332.

MS m/z 760 (M+H)⁺

Example 333(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10ml) was added dropwise to a precooled (0° C.) solution of sodium2-pyrrolidinoethoxide in DMF (50 ml), which was made by stirring amixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) andN-(2-hydroxyethyl)pyrrolidine (1.72 g, 15.0 mmol). The resultingreaction mixture was warmed to rt and stirred for additional 3 h. To thesame reaction flask was introduced potassium carbonate (2.10 g, 15.0mmol) and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and thereaction mixture was heated at 90° C. as described in the GeneralProcedure E for 2-alkoxy-4-aryloxybenzaldehydes. The crude product waspurified by silica gel column chromatography using dichloromethane and5% methanol in dichloromethane as eluent, to give2-(2-pyrrolidineethoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde(2 g) as a brown oil.

MS m/z 399 (M+H)⁺

Example 333 was formed employing the aldehyde formed above (873 mg; 2.2mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (848; 2.0mmol) following the general procedure K. The crude product was purifiedby silica gel column chromatography using 10% MeOH in DCM with a gradualincrement of triethylamine (0.2 to 1.0%) as eluent to afford 390 mg ofExample 333.

MS m/z 800 (M+H)⁺

Example 334{3-[1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine

MsCl (1.4 mL, 18.0 mmol) was added dropwise at 0° C. to a stirredsolution of pyrrolidineehanol (1.90 mL, 16.0 mmol), TEA (2.8 mL, 20.0mmol) in anhydrous DCM (20 mL), and the mixture was stirred at rt for 1h. After the removal of the solvent in vacuo, the solid residue wasmixed with 3,5-difluoro-4-nitrophenol (1.75 g; 10 mmol) and K2CO3 (5.5g; 40 mmol) following General Procedure F1. The product,2,6-difluoro-4-(N-pyrrolidineethoxy)nitrobenzene (1.5 g) was useddirectly.

To a stirred solution of2,6-difluoro-4-(N-pyrrolidineethoxy)nitrobenzene obtained above (1.4 g;5.1 mmol) and triethylamine (1.4 mL; 10.0 mmol) in DMF (10 mL), asolution of n-butylamine (505 μL; 5.1 mmol) in DMF (3 mL) was addedaccording to General Procedure G1. The crude product,2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-fluoronitrobenzene. (1.5 g)was used for further transformation without any purification.

A solution of 3-diethylaminopropanol (652 μL; 4.4 mmol) in anhydrous THF4.4 mL was added with powdered KOBu^(t) (493 mg; 4.4 mmol) and stirredat rt for 5 min. This solution was added dropwise to a stirred solutionof 2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-fluoronitrobenzene (1.32g; 4.0 mmol) in anhydrous THF (10 mL) according to General Procedure G2.The crude product,2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)nitrobenzene.(1.5 g) was used directly.

The nitro compound formed above (1.31 g, 4 mmol) dissolved in MeOH (20mL) was hydrogenated following general procedure H. The product obtained(1.15 g) was used directly for the next step.

Example 334 was formed employing phenylenediamine formed above (816 mg;2 mmol) and2-(2-pyrrolidineethoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde(873 mg; 2.2 mmol) in ethanol (5 mL) following general procedure K. Thecrude product was purified by silica gel column chromatography using 10%MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) aseluent to afford 375 mg of Example 334.

MS m/z 784 (M+H)⁺

Example 335{3-[2-[1-Butyl-6-(3-diethylamino-propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10ml) was added dropwise to a precooled (0° C.) solution of sodium3-diethylaminopropoxide in DMF (50 ml), which was made by stirring amixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) and3-diethylaminopropanol (1.97 g, 15.0 mmol). The resulting reactionmixture was warmed to rt and stirred for additional 3 h. To the samereaction flask was introduced potassium carbonate (2.10 g, 15.0 mmol)and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the reactionmixture was heated at 90° C. as described general procedure E. The crudeproduct was purified by silica gel column chromatography usingdichloromethane and 5% methanol in dichloromethane as eluent, to give2-(3-diethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde(2.2 g).

Methanesulfonyl chloride (General Procedure P2) (1.55 mL, 20.0 mmol) wasadded dropwise at 0° C. to a stirred solution of 3-diethylaminopropanol(2.70 mL, 18.0 mmol), TEA (2.8 mL, 20.0 mmol) in anhydrous DCM (30 mL),and the mixture was stirred at rt for 1 h. After the removal of thesolvent in vacuo, the solid residue was mixed with3,5-difluoro-4-nitrophenol (2.65 g; 15 mmol) and K₂CO₃ (6.9 g; 50 mmol)according to General Procedure F1. The crude product,2,6-difluoro-4-(3-diethylaminopropoxy)nitrobenzene (3.9 g) was used forfurther transformation.

To a stirred solution of2,6-difluoro-4-(3-diethylaminopropoxy)nitrobenzene obtained above (1.9g; 6.6 mmol) and triethylamine (1.4 mL; 10.0 mmol) in DMF (12 mL), asolution of n-butylamine (656 μL; 6.6 mmol) in DMF (4 mL) was addeddropwise at rt within 15 min, and the rest was followed as described inthe general methods. The crude product,2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-fluoronitrobenzene (2.0 g)was used for further transformation without any purification.

A solution of 3-diethylaminopropanol (516 □L; 4.4 mmol) in anhydrous THF4.4 mL was added with powdered KOBu^(t) (493 mg; 4.4 mmol) and stirredat room temperature for 5 min. This solution was added dropwise to astirred solution of2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-fluoronitrobenzene (1.37 g;4.0 mmol) in anhydrous THF (10 mL) at 0° C. under a N₂ stream. Thereaction mixture was maintained at 0° C. for 1 h at which time thereaction was complete the rest was followed as described in the generalmethods. The crude product,2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-(N-pyrrolidineethoxy)nitrobenzene.(1.6 g) was used for further transformation without any purification.

The nitro compound formed above (1.31 g, 4 mmol) dissolved in MeOH (20mL) was hydrogenated following the general procedure and2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)aniline(1.15 g) obtained was used directly for the next step reaction withoutfurther purification. Example 335 was formed employing phenylenedimaineformed above (816 mg; 2 mmol) and2-(3-diethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde(910 mg; 2.2 mmol) in ethanol (5 mL) following the general procedure.The crude product was purified by silica gel column chromatography using10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%)as eluent to afford 380 mg of Example 335.

MS m/z 800 (M+H)⁺

Example 336{3-[2-[1-Butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10ml) was added dropwise to a precooled (0° C.) solution of sodium3-dimethylaminopropoxide in DMF (50 ml), which was made by stirring amixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) and3-dimethylaminopropanol (1.55 g, 15.0 mmol). The resulting reactionmixture was warmed to rt and stirred for additional 3 h. To the samereaction flask was introduced potassium carbonate (2.10 g, 15.0 mmol)and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the reactionmixture was heated at 90° C. as described in General Procedure E for2-alkoxy-4-aryloxybenzaldehydes. The crude product was purified bysilica gel column chromatography using dichloromethane and 5% methanolin dichloromethane as eluent, to give2-(3-dimethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde(2.0 g).

Example 336 was formed employing the aldehyde formed above (823 mg; 2.2mmol) and 2-butylamino-4,6-di(pyrrolidineethoxy)aniline (784; 2.0 mmol)in ethanol (5 mL) following General Procedure K. The crude product waspurified by silica gel column chromatography using 10% MeOH in DCM witha gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford380 mg of Example 336.

MS m/z 784 (M+H)⁺

Example 337{3-[3-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10ml) was added dropwise to a precooled (0° C.) solution of sodium3-dimethylaminopropoxide in DMF (50 ml), which was made by stirring amixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) and3-dimethylaminopropanol (1.55 g, 15.0 mmol). The resulting reactionmixture was warmed to rt and stirred for additional 3 h. To the samereaction flask was introduced potassium carbonate (2.10 g, 15.0 mmol)and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the reactionmixture was heated at 90° C. as described in General Procedure E for2-alkoxy-4-aryloxybenzaldehydes. The crude product was purified bysilica gel column chromatography using dichloromethane and 5% methanolin dichloromethane as eluent, to give2-(3-dimethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde(2.0 g).

Example 337 was formed employing the aldehyde formed above (823 mg; 2.2mmol) and 2-butylamino-4,6-di(pyrrolidineethoxy)aniline (784; 2.0 mmol)in ethanol (5 mL) following General Procedure K. The crude product waspurified by silica gel column chromatography using 10% MeOH in DCM witha gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford380 mg of Example 337.

MS m/z 759 (M+H)⁺

Example 338(3-{2-[1-Butyl-4-(3-diethylamino-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine

2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (858;2.2 mmol) and2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)aniline(816 mg; 2 mmol) were condensed to form the benzimidazole followingGeneral Procedure K. The crude product was purified by silica gel columnchromatography using 10% MeOH in DCM with a gradual increment oftriethylamine (0.2 to 1.0%) as eluent to afford 390 mg of Example 338.

MS m/z 776 (M+H)⁺

The following Examples were synthesized according to the Methodsemployed for Examples 327-338;

Example Name 339{3-[1-butyl-2-[4-(3,4-dichloro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 340{3-[2-[2,4-bis-(3-diethylamino-propoxy)-phenyl]-1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 341{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yl]-phenyl}-diethyl-amine 342{3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 3431-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 344{3-[1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 345(3-{6-(3-Diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 346{3-[2-[1-Butyl-4-(3-diethylamino-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 347{3-[3-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine 348{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 349{3-[2-[1-butyl-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine 350{3-[1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-3-diethylaminomethyl-phenyl}-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 351{3-[2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yl]-propyl}-diethyl-amine 3523-(7-Butoxy-3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-cyclopentylmethoxy-phenyl}-3H-benzoimidazol-5-yloxy)-propan-1-ol 3533-(7-Butoxy-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-cyclopentylmethoxy-phenyl}-3H-benzoimidazol-5-yloxy)-propan-1-ol 354(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 355{3-[2-[1-Butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 3562-(3,5-bis-benzyloxy-phenyl)-1-butyl-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzimidazole 357{3-[2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine 3581-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrol-1-yl-ethoxy)-phenyl]-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzoimidazole 359{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl}-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 360{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-3-ylmethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 361(3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl]-7-isopropoxy-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 362{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 363{3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 3641-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 3652-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,7-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 366{3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-methoxy-phenyl}-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine367 {3-[2-{4-[2-(4-Chloro-phenyl)-ethoxy]-2-methoxy-phenyl}-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine368(3-{1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl]-6-isopropoxy-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 369{3-[1-Butyl-2-[4-(4-chloro-3-methyl-phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 3701-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 371(2-{1-butyl-6-(2-dimethylamino-ethoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}-ethyl)-dimethyl-amine 3722-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenol 3731-Butyl-2-[4-(4-chloro-3-methyl-phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 3742-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 3752-[4-(4-Fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 376{3-[2-(3,5-bis-benzyloxy-phenyl)-1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 377(3-{1-butyl-6-(3-dimethylamino-propoxy)-2-[4-(3-fluoro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}-propyl)-diethyl-amine 378{3-[2-{1-butyl-4-(4-chloro-benzyloxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 379{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl]-6-(3-diethylamino-propoxy)-3H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 380{3-[2-[4-(3,4-dichloro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 381{3-[1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 382{3-[2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 383(3-{1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 3842-{2,4-bis-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 385(2-{1-butyl-6-(2-dimethylamino-ethoxy)-2-[4-(3-fluoro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}-ethyl)-dimethyl-amine 386{3-[2-[4-(3,5-bis-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 387{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 388(3-{2-(1-Butyl-4,6-diisopropoxy-1H-benzoimidazol-2-yl)-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 389{3-[1-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-4-diethylaminomethyl-phenyl}-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 390(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-fluoro-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 391(2-{1-butyl-6-fluoro-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine 392{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-3-(3-diethylamino-propoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine

Example 393(4-benzyloxy-benzyl)-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-ylmethyl]-hexyl-amine

To 2-butylamino-4-(3-diethylaminopropoxy)aniline (3.44 g; 11.7 mmol) andBOC-glycine (2.46 g, 14.1 mmol) in DCM (20 mL) was added DCC (2.90 g,14.1 mmol) and the reaction mixture was stirred for 4 h. The solid wasremoved by filtration and the filtrate was concentrated to afford thedesired product. The crude product was used for further transformationwithout any purification.

To the product (11.7 mmol) obtained above in dioxane (7.5 mL) was addedacetic acid (2.5 mL) and the reaction mixture was heated at 80° C. untilthe reaction was complete. Saturated sodium bicarbonate was added andthe mixture was extracted with EtOAc. The combined organic layer waswashed with water and brine, dried over sodium sulfate. Evaporation ofthe solvent in vacuo afforded desired1-butyl-2-boc-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole.The product obtained was treated with 4 N HCl in dioxane according toGeneral Procedure H to give1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazolehydrochloride.

To 1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (1.0mmol) in DCM (8 mL) were added Et₃N (3.0 mmol) and 4-benzoxybenzaldehyde(1.0 mmol) and the mixture was stirred for 4 h, then NaBH(OAc)₃ (4.0mmol) was added and stirred for another 4 h, then sodium bicarbonate wasadded and the mixture was extracted with EtOAc. The combined organiclayer was washed with brine, and dried over sodium sulfate. The crudeproduct was purified by silica gel column chromatography using DCM witha gradual increment of MeOH (1% to 10%) as eluent to afford1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropoxy)-1-H-benzimidazole.

To1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole(16 mg, 0.03 mmol) in DCM (2 mL) were added hexanal (8.3 mg, 0.083 mmol)and the mixture was stirred for 10 min, then NaBH(OAc)₃ (32 mg, 0.15mmol) was added and stirred for 3 h, then sodium bicarbonate was addedand the mixture was extracted with EtOAc (3×10 mL). The combined organiclayer was washed with brine, and dried over sodium sulfate. The crudeproduct was purified by silica gel column chromatography using DCM witha gradual increment of MeOH (1% to 5%) as eluent to afford 14 mg ofExample 393.

MS m/z 613 [M+H]⁺

Example 394(4-benzyloxy-benzyl)-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-ylmethyl]-isobutyl-amine

To1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole(16 mg, 0.03 mmol) in DCM (2 mL) were added isbutrylaldehyde (8.6 mg,0.10 mmol) and the mixture was stirred for 10 min, then NaBH(OAc)₃ (32mg, 0.15 mmol) was added and stirred for 3 h, then sodium bicarbonatewas added and the mixture was extracted with EtOAc. The combined organiclayer was washed with brine, and dried over sodium sulfate. The crudeproduct was purified by silica gel column chromatography using DCM witha gradual increment of MeOH (1% to 5%) as eluent to afford 12 mg ofExample 394.

MS m/z 585 [M+H]⁺

Example 395[3-(2-[(4-benzyloxy-benzyl)-cyclopentylmethyl-amino]-methyl}-3-butyl-3-H-benzimidazol-5-yloxy)-propyl]-diethylamine

To1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole(16 mg, 0.03 mmol) in DCM (2 mL) were added cyclopentyl carboxaldehyde(11 mg, 0.10 mmol) and the mixture was stirred for 10 min, thenNaBH(OAc)₃ (32 mg, 0.15 mmol) was added and stirred for 3 h, then sodiumbicarbonate was added and the mixture was extracted with EtOAc (3×10mL). The combined organic layer was washed with brine, and dried oversodium sulfate. The crude product was purified by silica gel columnchromatography using DCM with a gradual increment of MeOH (1% to 5%) aseluent to afford 8.0 mg of Example 395.

MS m/z 611 [M+H]⁺

Example 396

N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-ylmethyl]-benzamide

To1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole(32 mg, 0.06 mmol) in DCM (3 mL) were added benzoyl chloride (34 mg,0.24 mmol), TEA (24 mg, 0.24 mmol), DMAP (catalytic amount) and themixture was stirred for 12 h, then sodium bicarbonate was added and themixture was extracted with EtOAc (3×10 mL). The combined organic layerwas washed with brine, and dried over sodium sulfate. The crude productwas purified by silica gel column chromatography using DCM with agradual increment of MeOH (0 to 1%) as eluent to afford 30 mg of Example396.

MS m/z 633 [M+H]⁺

Example 397(3-{3-butyl-2-[(dibenzylamino)-methyl]-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine

To 1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (15mg, 0.034 mmol) in DCM (2 mL) were added Et₃N (0.10 mmol) andbenzaldehyde (180 mg, 0.17 mmol) and the mixture was stirred for 10 min,then NaBH(OAc)₃ (72 mg, 0.34 mmol) was added and stirred for 3 h, thensodium bicarbonate was added and the mixture was extracted with EtOAc.The combined organic layer was washed with brine, and dried over sodiumsulfate. The crude product was purified by silica gel columnchromatography using DCM with a gradual increment of MeOH (1% to 2%) aseluent to afford 10 mg of Example 397.

MS m/z 513 [M+H]⁺

The following Examples were synthesized according to the Methodsemployed for Examples 393-397;

Example Name 398 (3-{2-[(4-benzyloxy-benzylamino)-methyl]-3-butyl-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 399N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-ylmethyl]-methanesulfonamide 400N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-ylmethyl]-acetamide 401{3-[3-butyl-2-({4-[2-(4-chloro-phenyl)-ethoxy]-benzylamino}-methyl)-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 402[3-(2-{[Bis-(4-benzyloxy-benzyl)-amino]-methyl}-3-butyl-3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine 403[3-(2-{[Benzyl-(4-benzyloxy-benzyl)-amino]-methyl}-3-butyl-3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine

Example 404{3-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O andextracted with EtOAc. The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of the solvent in vacuuoafforded the desired 4-alkoxynitrobenzene.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg), according to General Procedure H. The reaction mixturewas then filtered to remove the catalyst. The solvent was removed invacuuo to afford the desired 4-alkoxyaniline, which was used directlyfor further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion, according to General Procedure Q1. After cooling tort, the reaction mixture was quenched using cold water (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml)and brine (15 ml). The organic layer was dried over magnesium sulfate,and the solvent was removed in vacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of valeryl chloride (2eq., 3.2 mmol), according to General Procedure R3. The reaction mixturewas stirred under nitrogen at 0° C. for 1 h and allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The reaction mixture wasthen diluted with cold water and the product was isolated in DCM. Thesolvent was removed in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography on silica gel (yield: 270 mg).

MS m/z 561 (M+H)⁺:

¹H NMR: δ 7.85 (s, 1H), 7.71 (d, 2H), 7.56 (d, 2H), 7.32 (m, 4H), 7.24(d, 2H), 7.06 (d, 2H), 4.25 (t, 2H), 3.43 (t, 2H), 3.35 (m, 6H), 3.12(t, 2H), 2.97 (t, 2H), 2.31 (m, 2H), 1.65 (m, 2H), 1.41 (t, 6H), 1.37(m, 2H), 0.85 (t, 3H) ppm.

Example 405{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. until completion, as indicated by TLC or HPLC. The reactionmixture was then treated with cold H₂O (15 mL), and extracted with EtOAc(2×15 mL). The combined organic layers were washed with brine and driedover sodium sulfate. Evaporation of the solvent in vacuuo afforded thedesired 4-alkoxynitrobenzene. The crude product was used directly forfurther transformation without any purification, or after purifyingusing silica gel column chromatography.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (1.2 mmol) in DMF (10mL) at rt, solid potassium carbonate (3.0 mmol) was added.4-chlorophenethyl mesylate (1.0 mmol) was added to the reaction mixtureand heated to 80° C. until completion according to General Procedure Q1,as indicated by TLC or HPLC. After cooling to rt, the reaction mixturewas quenched by removing solvent in vacuuo and treating the residue withsaturated sodium bicarbonate. The aqueous layer was poured into EtOAc(20 ml) and washed with H₂O (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation without anypurification or after purifying using silica gel column chromatography.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added,according to General Procedure R1. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and was allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was then removed invacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq, 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold H₂O and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-4% MeOH/DCM.

To a stirred solution of1-{-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq, 6mmol) was added, followed by a slow addition of isovaleryl chloride (3eq, 6 mmol), according to General Procedure R3. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (Yield: 390 mg).

MS m/z 560 (M+H)⁺

¹H NMR: δ 7.86 (s, 1H), 7.65 (d, 2H), 7.59 (d, 2H), 7.31 (m, 4H), 7.23(d, 2H), 7.13 (d, 2H), 4.51 (m, 2H), 3.42 (t, 2H), 3.31 (m, 6H), 3.05(t, 2H), 2.87 (t, 2H), 2.31 (m, 2H), 1.95 (m, 1H), 1.49 (t, 6H), 0.86(d, 6H) ppm.

Example 406[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture stirred at 0° C. for an hour andat rt for another hour (until the reaction was complete by HPLC). Thesolvent was removed and saturated aqueous sodium bicarbonate was added.The product was extracted with EtOAc (3×) and washed with sodiumbicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL), and 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was extracted with EtOAcand washed with sodium bicarbonate and water. The solvent was removed invacuuo and the product was purified by flash chromatography (going byincreasing gradient up to 10% MeOH in DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(5 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide(6 mmol, 1.2 eq) was added, according to General Procedure R1. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and wasallowed to warm to rt until completion, as indicated by TLC or HPLC. Thesolvent was then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-chlorophenoxy aniline (1 eq, 5 mmol) in anhydrous DMF(10 mL), DIEA (3 eq 15 mmol) was added, followed by addition of the2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described above(5 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at it until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM.

To a stirred solution of2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone(2 mmol) in anhydrous DCM (8 mL) at 0° C., TEA (3 eq, 6 mmol) was added,followed by a slow addition of valeryl chloride (3 eq, 6 mmol). Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to it until completion as indicated by TLC or HPLC, according toGeneral Procedure R3. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (2 mmol) in aceticacid (8 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography onsilica gel elution with 4-6% MeOH/DCM) (yield 424 mg).

MS m/z 532 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.68 (d, 2H), 7.34 (d, 2H), 7.28 (d, 2H), 7.14 (s,1H), 7.07 (d, 2H), 7.01 (d, 2H,), 6.89 (d, 2H) 4.04 (t, 2H), 2.64-2.78(m, 8H), 1.99 (m, 2H), 1.64 (m, 2H), 1.30 (m, 2H), 1.09 (t, 6H), 0.83(t, 3H) ppm.

Example 4071-[4-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-butyl]piperazine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added. The reaction mixture was stirred under nitrogen atrt until completion, as indicated by TLC. The mixture was diluted withEtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and driedwith magnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromoacetophenone was used for furthertransformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the alpha-bromoacetophenone described above (2 eq),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at it until completion, as indicated by TLC and HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in Et₂O. The combined organic layers were washed with brine anddried over sodium sulfate. Evaporation of solvent in vacuuo afforded thedesired product. The crude alkylated aniline was purified bychromatography on silica gel (elution with 5-20% EtOAc/Hexane).

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol). The reactionmixture was stirred under nitrogen at 0° C. for 1 h and allowed to warmto ambient temperature until completion as indicated by TLC and HPLC,according to General Procedure R3. The solvent was removed in vacuuo,and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography on silica gel (elution with 5-15% EtOAc/Hexane). MS: m/z562 (M+H)⁺)

The benzyl imidazole from above was dissolved in MeOH (20 mL), and Pd/C(100 mg) was added and the heterogeneous mixture was stirred overnightunder hydrogen atmosphere using a balloon, according to GeneralProcedure H. The catalyst was removed by filtration. The solvent wasremoved in vacuuo, and the crude phenol (MS: m/z 472 (M+H)⁺) was useddirectly.

To a stirred solution of the phenol (0.16 mmol) obtained above inanhydrous DMF (5 mL) solid sodium hydride (60% dispersion in oil; 1.0mmol) was added in portions. After the addition, a solution of4-bromobutyl methanesulfonate (0.2 mmol) (prepared as described earlier)in anhydrous THF (2 mL) was added to the reaction mixture. The reactionwas then allowed to proceed at rt. Upon completion of the reaction,piperazine (5.0 eq) was added. The mixture was stirred overnight. Et₂O(30 mL) was added to the reaction mixture followed by H₂O (10 mL). Theorganic layer was washed with H₂O (2×15 mL) and brine, and dried oversodium sulfate. The solvent was removed in vacuuo. Product was purifiedby column chromatography on silica gel (elution with 5-10% MeOH/DCM)(yield 54.0 mg)

MS m/z 612 (M+1-1)⁺:

Example 4084-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-1-methyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at rt until completion, as indicatedby TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O(2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solventwas then removed in vacuuo to give a white solid. Thealpha-bromoacetophenone was used for further transformation withoutfurther purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the alpha-bromoacetophenone described above (2 eq),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC and HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in Et₂O. The combined organic layers were washed with brine anddried over sodium sulfate. Evaporation of solvent in vacuuo afforded thedesired product. The crude alkylated aniline was purified bychromatography on silica gel (elution with 5-20% EtOAc/Hexane).

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion. The solventwas removed in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography on silica gel (elution with 5-15% EtOAc/Hexane).

MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) wasadded and the heterogeneous mixture was stirred overnight under hydrogenatmosphere using a balloon, according to General Procedure T2. The Pd/Cwas removed by filtration. The solvent was removed in vacuuo, and thecrude4-(1-{-4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol(MS: m/z 472 (M+H)⁺) was used directly.

A stirred solution of the4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol), added in portions. The mesylate of1-methylpiperidin-4-ol (1.5-2.0 eq) was then added to the reactionmixture, which was heated at 90° C. overnight, according to GeneralProcedure T3. After cooling the mix to rt, Et₂O (30 mL) was added to thereaction mixture followed by H₂O (10 mL). The organic layer was washedwith H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solventwas removed in vacuuo. Pure imidazole was obtained from chromatographyin 5-10% MeOH/DCM (yield 14 mg).

MS m/z value (M+H)⁺: 569

¹H NMR (CDCl₃): δ7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08 (d,2H), 6.92 (d, 2H), 4.4 (bs, 1H), 1.0 3.05 (m, 17H) ppm.

Example 4091-[5-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-pentyl]piperazine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added. The reaction mixture was stirred under nitrogen atrt until completion, as indicated by TLC. The mixture was diluted withEtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and driedwith magnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromoacetophenone was used for furthertransformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the alpha-bromoacetophenone described above (2 eq),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC and HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in Et₂O. The combined organic layers were washed with brine anddried over sodium sulfate. Evaporation of solvent in vacuuo afforded thedesired product. The crude alkylated aniline was purified bychromatography (Silica gel). Pure product was obtained from 5-20%EtOAc/Hexane.

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by TLC and HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 5-15%EtOAc/Hexane.

MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) wasadded and the heterogeneous mixture was stirred overnight under hydrogenatmosphere using a balloon, according to General Procedure H. The Pd/Cwas removed by filtration. The solvent was removed in vacuuo, and thecrude phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

To a stirred solution of the imidazole (0.16 mmol) obtained above inanhydrous DMF (5 mL) solid sodium hydride (60% dispersion in oil; 1.0mmol) was added in portions. After the addition, a solution of5-bromopentyl methanesulfonate (0.2 mmol) anhydrous THF (2 mL) was addedto the reaction mixture. The reaction was then allowed to proceed at rt.Upon completion of the reaction, piperazine (100 mg) added. The mixturewas stirred overnight. Et₂O (30 mL) was added to the reaction mixturefollowed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL)and brine, and dried over sodium sulfate. The solvent was removed invacuuo. Pure product was obtained after chromatography on silica gel(elution with 5-10% MeOH/DCM) (yield 36.0 mg).

MS m/z 626 (M+H)⁺:

Example 410{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. until completion, as indicated by TLC or HPLC. The reactionmixture was then treated with cold H₂O (15 mL), and extracted with EtOAc(2×15 mL). The combined organic layers were washed with brine and driedover sodium sulfate. Evaporation of the solvent in vacuuo afforded thedesired 4-alkoxynitrobenzene. The crude product was used directly forfurther transformation without any purification, or after purifyingusing silica gel column chromatography.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desiredN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine, which was used directlyfor further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (1.2 mmol) in DMF (10mL) at rt, solid potassium carbonate (3.0 mmol) was added.4-chlorophenethyl mesylate (1.0 mmol) was added to the reaction mixtureand heated to 80° C. until completion according to General Procedure Q1,as indicated by TLC or HPLC. After cooling to rt, the reaction mixturewas quenched by removing solvent in vacuuo and treating the residue withsaturated sodium bicarbonate. The aqueous layer was poured into EtOAc(20 ml) and washed with H₂O (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidinone hydrotribromide (1.2 eq) was added,according to General Procedure R1. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and was allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was then removed invacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq, 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold H₂O and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-4% MeOH/DCM.

The1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanoneobtained as above (1 mmol) was dissolved in formic acid (2 mL) andtreated with ammonium formate (20 mmol). The resulting mixture washeated to 90° C. overnight. The reaction mixture was then cooled to rtand neutralized with saturated sodium bicarbonate solution. Usualextractive work up with EtOAc gave the product imidazole, which waspurified by column chromatography on silica gel (elution with 4-6%MeOH/DCM) (yield 161 mg).

MS m/z 504 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.77 (s, 1H), 7.73 (d, 2H), 7.38 (s, 1H), 7.10-7.35(m, 6H), 6.97 (d, 2H), 6.92 (d, 2H), 4.17 (t, 2H), 4.06 (broad t, 2H),3.07 (t, 2H), 2.81 (broad q, 4H) 1.95-2.15 (broad m, 4H), 1.17 (t, 6H)ppm.

Example 411{3-[3-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 3-nitrophenol (2 mmol) in DMF (6 mL) at rt,solid potassium carbonate (4 mmol) was added. A solution of the mesylateof N,N-diethylaminopropanol (2.2 mmol) in DMF (2 mL) was then added tothe reaction mixture and heated to 80° C. until completion, according toGeneral Procedure Q1, as indicated by TLC or HPLC. After cooling to rt,the reaction mixture was then treated with cold H₂O (15 mL), andextracted with EtOAc (2×15 mL). The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desiredN,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine. The crude product wasused directly for further transformation.

The N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine (1 mmol) was dissolvedin MeOH (5 mL) and hydrogenated in the presence of 10% Pd/C (50 mg)until completion as indicated by TLC or HPLC, according to GeneralProcedure H. The reaction mixture was then filtered to remove thecatalyst. The solvent was removed in vacuuo to afford the desiredN-[3-(3-aminophenoxy)propyl]-N,N-diethylamine, which was used directlyfor further transformation without further purification.

To a stirred solution of N-[3-(3-aminophenoxy)propyl]-N,N-diethylamine(1 mmol) in anhydrous DMF (3 mL), DIEA (3 mmol) was added followed by aslow addition of 1-bromo-4′-(4-chlorophenethoxy)acetophenone (0.8 mmol),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in EtOAc. The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of solvent in vacuuo affordedthe desired product. The crude alkylated aniline was purified bychromatography on silica gel (elution with 2-4% MeOH/DCM).

The1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanoneobtained as above (0.5 mmol) was dissolved in formic acid (1 mL) andtreated with ammonium formate (10 mmol). The resulting mixture washeated to 90° C. overnight. The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate solution. Usualextractive work up with EtOAc gave the product imidazole, which waspurified by column chromatography on silica gel (elution with 4-6%MeOH/DCM).

MS m/z value (M+H)⁺: 504

¹H NMR (CDCl₃): δ7.89 (s, 1H), 7.74 (d, 2H), 7.47 (s, 1H), 7.30-7.10 (m,7H), 6.92 (d, 2H) 6.85 (t, 1H) 4.10-4.20 (m, 4H), 3.00-3.20 (m, 6H),2.31 (broad, 2H), 1.36 (t, 6H) ppm.

Example 412[3-(4-{1-[4-(4-tert-butyl-phenoxy)-phenyl]-1H-imidazol-4-yl)-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of potassium 4-tert-butyl-phenoxide(2.2 mmol) in THF (may be generated by adding the corresponding alcoholto a 1M solution of KOBu^(t) in THF) was added dropwise and under anitrogen stream, according to General Procedure L1. The reaction mixturewas stirred at 0° C. until completion, as indicated by TLC or HPLC. Thesolvent was then removed in vacuo and the reaction mixture was treatedwith cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combinedorganic layers were washed with brine and dried over sodium sulfate.Evaporation of the solvent in vacuuo afforded the desired4-alkoxynitrobenzene. The crude product was used directly for furthertransformation.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion, as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered. The solvent was removed invacuuo to afford the desired 4-alkoxyaniline, which was used directlyfor further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10mL) at rt, solid K₂CO₃ (8.0 mmol) was added. The mesylate ofN,N-diethylaminopropanol (prepared from the corresponding alcohol andmethanesulfonyl chloride, 2.0 mmol) was added to the reaction mixtureand heated to 80° C. until completion according to General Procedure Q1,as indicated by TLC or HPLC. After cooling to rt, the reaction mixturewas diluted with H₂O and the product was isolated in EtOAc. The combinedorganic layers were washed with saturated sodium bicarbonate (2×15 ml),water (2×15 ml) and brine (15 ml). The organic layer was dried overmagnesium sulfate, and the solvent was removed in vacuuo to afford thedesired product. The crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanonewas purified using silica gel column chromatography (elution with 2-3%MeOH/DCM).

To a stirred solution of the1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (1 mmol) described above48% HBr (3 eq, 3 mmol) in DMSO (4 mL) was added. The reaction mixturewas heated to 80° C. until completion, as indicated by TLC or HPLC.After cooling to rt, the reaction mixture was neutralized with 2N sodiumhydroxide solution and the product was isolated in EtOAc. The combinedorganic layers were washed with H₂O (2×15 ml) and brine (15 ml). Theorganic layer was dried over magnesium sulfate, and the solvent wasremoved in vacuuo to afford the desired product. The crude ketoaldehydewas used for further transformation.

To a stirred solution of the ketoaldehyde (1 mmol) in AcOH (5 mL)4-tert-butyl-phenoxy aniline (1.2 eq., 1.2 mmol), formaldehyde (excess,˜30 eq.) and ammonium acetate (excess, ˜30 eq.) were added, according toGeneral Procedure R4. The reaction mixture was heated to 80° C. untilcompletion, as indicated by TLC or HPLC. After cooling to rt, thereaction mixture was neutralized with saturated sodium bicarbonatesolution and the product was isolated in EtOAc. Usual extractive work upgave the desired product, which was purified by column chromatography onsilica gel (elution with 3-4% MeOH/DCM) (Yield 150 mg).

MS: m/z 498 (M+H)⁺

¹H NMR (CDCl₃): δ7.64 (s, 1H), 7.39 (d, 2H), 7.12 (s, 1H), 7.06 (d, 2H)7.02 (d, 2H) 6.97 (m, 2H) 6.79 (d, 2H), 3.98 (t, 2H), 2.66 (m, 6H), 2.02(m, 2H), 1.31 (s, 9H), 1.08 (t, 6H) ppm.

Example 413[3-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generatedby adding the corresponding alcohol to a 1M solution of potassiumt-butoxide in THF) was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. until completion, as indicated by TLC or HPLC. The solvent wasthen removed in vacuuo and the reaction mixture was treated with coldH₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof the solvent in vacuuo afforded the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct could be used directly for further transformation.

The 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene (2 mmol)obtained above was dissolved in MeOH (10 mL) and hydrogenated in thepresence of 10% Pd/C (10 mg) until completion, as indicated by TLC orHPLC, according to General Procedure H. The reaction mixture was thenfiltered. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylateof N,N-diethylaminopropanol (prepared from the corresponding alcohol andmethanesulfonyl chloride) (2.0 mmol) was added to the reaction mixtureand heated to 80° C. until completion according to General Procedure Q1,as indicated by TLC or HPLC. After cooling to rt, the reaction mixturewas diluted with water and the product was isolated in EtOAc. Thecombined organic layers were washed with saturated sodium bicarbonate(2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer wasdried over magnesium sulfate, and the solvent was removed in vacuuo toafford the desired product. The crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified using silicagel column chromatography. Pure product was obtained after elution with2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1 mmol)in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq,1.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the residue was treated with saturatedsodium bicarbonate and the product was isolated in EtOAc. The combinedorganic layers were washed with water (2×15 ml) and brine (15 ml). Theorganic layer was dried over magnesium sulfate, and the solvent wasremoved in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of the 4-fluoro-3-trifluoromethyl-phenoxy aniline(1.2 eq., 1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3 mmol) wasadded, followed by slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(1.0 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3 mmol) was added, followedby slow addition of valeryl chloride (2 eq., 2.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with water and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained after elutionwith 4-6% MeOH/DCM (Yield 175 mg).

MS m/z 584 (M+H)⁺

Example 414

diethyl-[3-(4-{1-[4-(4-trifluoromethoxy-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of potassium4-trifluoromethoxy-phenoxide (2.2 mmol) in THF (may be generated byadding the corresponding alcohol to a 1M solution of KOBu^(t) in THF)was added dropwise under a nitrogen stream, according to GeneralProcedure L1. The reaction mixture was stirred at 0° C. untilcompletion, as indicated by TLC or HPLC. The solvent was then removed invacuo and the reaction mixture was treated with cold H₂O (15 mL), andextracted with EtOAc (2×15 mL). The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of the solvent invacuo afforded the desired 4-alkoxynitrobenzene. The crude product wasused directly for further transformation.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion, as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired 4-alkoxyaniline,which was used directly for further transformation without furtherpurification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10mL) at rt, solid K₂CO₃ (8.0 mmol) was added. The mesylate ofN,N-diethylaminopropanol (prepared from the corresponding alcohol andmethanesulfonyl chloride, 2.0 mmol) was added to the reaction mixtureand heated to 80° C. until completion according to General Procedure Q1,as indicated by TLC or HPLC. After cooling to rt, the reaction mixturewas diluted with H₂O and the product was isolated in EtOAc. The combinedorganic layers were washed with saturated sodium bicarbonate (2×15 ml),H₂O (2×15 ml) and brine (15 ml). The organic layer was dried overmagnesium sulfate, and the solvent was removed in vacuuo to afford thedesired product. The crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanonewas purified using silica gel column chromatography. Pure product wasobtained with 2-3% MeOH/DCM.

To a stirred solution of the1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (1 mmol) described above48% HBr (3 eq, 3 mmol) in DMSO (4 mL) was added. The reaction mixturewas heated to 80° C. until completion, as indicated by TLC or HPLC.After cooling to rt, the reaction mixture was neutralized with saturatedsodium bicarbonate solution and the product was isolated in EtOAc. Thecombined organic layers were washed with water (2×15 ml) and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crudeketoaldehyde was used for further transformation.

To a stirred solution of the ketoaldehyde (1 mmol) in AcOH (5 mL),4-trifluoromethoxy-phenoxy-aniline (1.2 eq., 1.2 mmol), formaldehyde(excess, ˜30 eq.) and ammonium acetate (excess, ˜30 eq.) were added,according to General Procedure R4. The reaction mixture was heated to80° C. until completion, as indicated by TLC or HPLC. After cooling tort, the reaction mixture was neutralized with saturated sodiumbicarbonate solution and the product was isolated in EtOAc. Usualextractive work up with EtOAc gave the desired product, which waspurified by column chromatography on silica gel, elution with 3-4%MeOH/DCM) (Yield 130 mg).

MS: m/z 526 (M+H)⁺

¹H NMR (CDCl₃): δ7.91 (s, 1H), 7.41 (d, 2H), 7.28 (d, 2H), 7.05 (d, 2H),6.98 (m, 4H) 6.81 (d, 2H) 3.99 (t, 2H), 2.96 (m, 6H), 2.18 (m, 2H), 1.22(t, 6H) ppm.

Example 415[3-(4-{2-butyl-1-[4-(3,4-dichloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at it for another hour (until the reaction was complete by HPLC).The solvent was removed and saturated aqueous sodium bicarbonate wasadded. The product was extracted with EtOAc (3×) and washed with sodiumbicarbonate and water. The solvent was removed in vacuuo.

The product from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and the1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flashchromatography (going by increasing gradient up to 10% MeOH in DCM).

3,4-Dichlorophenol (10 mmol) was dissolved in 15 ml of anhydrous DMF andpotassium carbonate (30 mmol) was added with stirring at rt.4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was thenheated under reflux at 80° C. for 18 h. The reaction was quenched with30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc(3×50 ml) and washed with sodium bicarbonate and water. The EtOAc layerwas dried over anhydrous sodium sulfate and filtered, after which thesolvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH(30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(3,4-dichlorophenoxy)aniline, which was used directly for furthertransformation without further purification.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(2.4 mmol, 1.2 eq) was added, according to General Procedure R1. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and wasallowed to warm to rt until completion, as indicated by TLC or HPLC. Thesolvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-(3,4-dichlorophenoxy) aniline (1 eq, 2 mmol) inanhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by additionof the 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone describedabove (2 mmol), according to General Procedure R2. The reaction mixturewas stirred under nitrogen at rt until completion, as indicated by TLCor HPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM.

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq) was added according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography on silica gel (elution with 4-6% MeOH/DCM) (yield 170mg).

MS m/z 567 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.3 (m, 3H), 6.9-7.1 (m, 7H),4.0 (t, 2H), 2.7 (m, 8H), 2.0 (m, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 1.1 (t,6H), 0.8 (t, 3H) ppm.

Example 416[3-(4-{2-cyclobutyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL), methanesulfonylchloride (60 mmol) was added dropwise and the reaction mixture wasstirred for 2 h at 0° C., followed by additional 1 h at rt. After theremoval of the solvents in vacuuo, the crude mesylate was dissolved inDMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100mmol) were added, and the mixture was heated with stirring at 90° C. for18 h (monitored by LC-MS). After cooling to rt, the reaction wasquenched with cold H₂O (100 mL), and the resulting mixture was extractedwith EtOAc (4×100 mL). The combined EtOAc extracts were washed withbrine (3×60 ml), and dried over anhydrous sodium sulfate. The solventwas removed in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was addedfollowed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was addedfollowed by a slow addition of cyclobutanecarbonyl chloride (0.6 mmol, 3eq), according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled tort and neutralized with saturated sodium bicarbonate. The resultingmixture was extracted with EtOAc (3×50 mL). The combined EtOAc extractswere washed with brine (3×20 mL), and dried over anhydrous sodiumsulfate. The solvent was removed in vacuuo, and the pure product wasobtained by silica gel column chromatography eluting with 10% MeOH inEtOAc+0.2% TEA (yield 64 mg).

MS m/z 582 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.05 (t, 6H), 1.90-2.20 (m, 6H), 2.56 (m, 2H),2.58 (q, 4H), 2.66 (t, 2H), 3.44 (m, 1H), 4.02 (t, 2H), 6.91 (d, 2H),7.05 (d, 2H), 7.14 (s, 1H), 7.22-7.26 (m, 3H), 7.31 (d, 2H), 7.72 (d,2H) ppm.

Example 417[3-(4-{2-cyclopentyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of cyclopentanecarbonyl chloride (0.6 mmol,3 eq), according to General Procedure R3. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(overall yield: 60-70%) (yield 77 mg).

MS m/z 596 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 1.03-2.00 (m, 11H), 1.07 (t, 6H), 2.59 (q,4H), 2.65 (t, 2H), 4.03 (t, 2H), 6.91 (d, 2H), 7.08 (d, 2H), 7.14 (s,1H), 7.24-7.27 (m, 3H), 7.33 (d, 2H), 7.71 (d, 2H) ppm.

Example 418[3-(4-{2-cyclohexyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification.

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of cyclohexanecarbonyl chloride (0.6 mmol, 3eq), according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(yield 74 mg).

MS m/z 610 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.02-2.00 (m, 13H), 1.06 (t, 6H), 2.60 (q,4H), 2.67 (t, 2H), 4.02 (t, 2H), 6.90 (d, 2H), 7.07 (d, 2H), 7.09 (s,1H), 7.22-7.26 (m, 3H), 7.30 (d, 2H,), 7.69 (d, 2H) ppm.

Example 419diethyl-[3-(4-{1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-propyl]-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of isovaleryl chloride (0.6 mmol, 3 eq),according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(yield 70 mg).

MS m/z 584 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.86 (d, 6H) 1.07 (t, 6H), 1.97 (m, 2H), 2.04(m, 1H), 2.55 (d, 2H), 2.61 (q, 4H), 2.69 (t, 2H), 4.03 (t, 2H), 6.90(d, 2H), 7.07 (d, 2H), 7.14 (s, 1H), 7.22-7.25 (m, 3H), 7.30 (d, 2H),7.70 (d, 2H) ppm.

Example 420[3-(4-{2-but-3-enyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of pent-4-enoyl chloride (0.6 mmol, 3 eq),according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(yield 58 mg).

MS m/z 582+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 1.12 (t, 6H), 2.03 (m, 2H), 2.45 (t, 2H),2.63 (t, 2H,), 2.73 (q, 4H), 2.77 (t, 2H), 4.04 (t, 2H), 4.94 (dd, 1H),5.00 (dd, 1H), 5.79 (m, 1H), 6.90 (d, 2H), 7.07 (d, 2H), 7.15 (s, 1H),7.24-7.25 (m, 3H), 7.32 (d, 2H, 7.70 (d, 2H) ppm.

Example 421[3-(4-{2-tert-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of pivaloyl chloride (0.6 mmol, 3 eq),according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(yield 76 mg).

MS m/z 584 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ1.09 (t, 6H), 1.24 (s, 9H), 1.99 (m, 2H), 2.64(q, 4H), 2.72 (t, 2H), 4.02 (t, 2H), 6.89 (d, 2H), 7.02 (s, 1H), 7.03(d, 2H), 7.23-7.25 (m, 3H), 7.35 (d, 2H), 7.69 (d, 2H) ppm.

Example 422diethyl-[3-(4-{2-(4-fluoro-phenyl)-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of 4-fluorobenzoyl chloride (0.6 mmol, 3eq), according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(overall yield: 60-70%) (yield 75 mg).

MS m/z 622 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.11 (t, 6H), 2.01 (m, 2H), 2.67 (q, 4H), 2.75(t, 2H), 4.05 (t, 2H), 6.93 (d, 2H), 6.98-7.26 (m, 7H), 7.01 (d, 2H),7.33 (s, 1H), 7.43 (d, 2H), 7.44 (d, 1H), 7.78 (d, 2H) ppm.

Example 423[3-(4-{1-[4-(3,5-bis-trifluoromethyl-phenoxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at rt for another hour (until the reaction was complete by HPLC).The solvent was removed and saturated aqueous sodium bicarbonate wasadded. The product was extracted with EtOAc (3×) and washed with sodiumbicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and the1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flashchromatography (going by increasing gradient up to 10% MeOH in DCM). Theoverall yield was 60%.

3,5-bis-trifluoromethylphenol (10 mmol) was dissolved in 15 ml ofanhydrous DMF and potassium carbonate (30 mmol) was added with stirringat rt. 4-Fluoronitrobenzene (10 mmol) was added to this mixture, whichwas then heated under reflux at 80° C. for 18 h. The reaction wasquenched with 30 ml of water and 30 ml of sodium bicarbonate, extractedwith EtOAc (3×50 ml) and washed with sodium bicarbonate and water. TheEtOAc layer was dried over anhydrous sodium sulfate and filtered, afterwhich the solvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH(30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(3,5-bis-trifluoromethyl)phenoxyaniline, which was used directly forfurther transformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-(3,5-bis-trifluoromethyl)phenoxyaniline (1 eq, 2mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed byaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (2 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Removal ofsolvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure productobtained from 2-4% MeOH/DCM (yield 50%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 139mg).

MS m/z 635 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.3 (m, 3H), 7.1 (m, 5H), 6.9(d, 2H), 4.0 (t, 2H), 2.6-2.8 (m, 8H), 2.0 (m, 2H), 1.6 (m, 2H), 1.3 (m,2H), 1.1 (t, 6H), 0.8 (t, 3H) ppm.

Example 424(3-{4-[1-(4-benzyloxy-phenyl)-2-butyl-1H-imidazol-4-yl]-phenoxy}propyl)-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at rt for another hour (until the reaction was complete by HPLC).The solvent was removed and saturated aqueous sodium bicarbonate wasadded. The product was extracted with EtOAc (3×) and washed with sodiumbicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and theproduct was purified by flash chromatography (going by increasinggradient up to 10% MeOH in DCM). The overall yield was 60%.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-benzyloxyaniline (1 eq, 2 mmol) in anhydrous DMF (6mL), DIEA (3 eq 6 mmol) was added, followed by addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield 56%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 205mg).

MS m/z 513 (M+H)⁺;

¹H NMR (CDCl₃): δ 7.68 (d, 2H), 7.40 (m, 5H), 7.23 (d, 2H), 7.11 (s,1H), 7.05 (d, 2H), 6.89 (d, 2H), 5.12 (s, 2H), 4.02 (t, 2H), 2.62-2.73(m, 8H), 1.98 (m, 2H), 1.63 (m, 2H), 1.28 (m, 2H), 1.07 (t, 6H), 0.82(t, 3H) ppm.

Example 425{3-[4-(2-tert-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained from 20-30%EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of pivaloyl chloride (2eq., 3.2 mmol), according to General Procedure R3. The reaction mixturewas stirred under nitrogen at 0° C. for 1 h and allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The reaction mixture wasthen diluted with cold water and the product was isolated in DCM. Thesolvent was removed in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield: 270 mg).

MS m/z 561 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.23-7.25 (m, 6H), 6.98 (s, 1H),6.84 (m 4H), 4.15 (t, 2H), 4.08 (t, 2H), 3.05 (t, 2H), 2.85 (m, 6H),2.16 (s, 9H), 2.05 (m, 2H), 1.19 (t, 6H) ppm.

Example 426[3-(4-{2-butyl-1-[4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added. The reaction mixture was stirred under nitrogen atrt until completion, as indicated by TLC. The mixture was diluted withEtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and driedwith magnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromoacetophenone was used for furthertransformation without further purification.

To a stirred solution of 4-(3-fluoro-4-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the alpha-bromoacetophenone described above (2 eq),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC and HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in Et₂O. The combined organic layers were washed with brine anddried over sodium sulfate. Evaporation of solvent in vacuuo afforded thedesired product. The crude alkylated aniline was purified bychromatography (Silica gel). Pure product was obtained from 5-20%EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by TLC and HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 5-15%EtOAc/Hexane (yield 80%). (MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) wasadded and the heterogeneous mixture was stirred overnight under hydrogenatmosphere using a balloon, according to General Procedure H. The Pd/Cwas removed by filtration. The solvent was removed in vacuuo, and thecrude phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

To a stirred solution of the phenol (1.0 eq) obtained above in anhydrousDMF (5.0 mL) solid sodium hydride (60% dispersion in oil; 1.0 mmol) wasadded in portions. After the addition, the requisite alkylhalide or themesylate (prepared from the corresponding alcohol and methanesulfonylchloride) (1.5-2.0 eq) was added to the reaction mixture. The reactionmixture was heated at 90° C. overnight. After cooling the mix to rt,Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL).The organic layer was washed with H₂O (2×15 mL) and brine, and driedover sodium sulfate. The solvent was removed in vacuuo. Pure product wasobtained from 5-10% MeOH/DCM (yield 65.0 mg).

MS m/z 557 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08(d, 2H), 6.92 (d, 2H), 4.02 (t, 2H), 2.66 (t, 2H), 2.47 (t, 2H), 2.26(s, 6H), 1.96 (m, 2H), 1.64 (m, 2H), 1.29 (m, 2H) 0.9 (t, 3H) ppm.

Example 427diethyl-[3-(4-{4-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine(1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added,followed by a slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product was obtained from2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) wasadded, according to General Procedure R4. The reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate solution. Usualextractive work up with EtOAc gave the product imidazole, which waspurified by column chromatography (Silica gel). Pure product wasobtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution ofN-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine(0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol),followed by potassium carbonate (0.35 mmol) and 4-fluoro-3-methylphenol(0.14 mmol). The mixture was heated at 110° C. overnight, then dilutedwith H₂O (2 mL) and extracted with EtOAc (3×2 mL). The combined organicextract was dried over sodium sulfate, filtered and concentrated to anoil, which was purified by column chromatography (Silica gel). The pureproduct was obtained from 1-6% MeOH/DCM.

MS m/z 528 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): ˜7.86-7.78 (m, 3H), 7.54-7.44 (m, 2H),7.38-7.34 (m, 2H), 7.28-7.24 (m, 1H), 7.20-7.16 (m, 2H), 7.06-6.80 (m,3H), 4.10 (t, 2H), 2.80-2.60 (m, 6H), 2.10-2.00 (m, 2H), 1.30 (t, 3H),1.10 (t, 3H) ppm.

Example 428(3-{-4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(4-fluoro-phenyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained from 20-30%EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of 4-fluorobenzoylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield: 334 mg).

MS m/z 598 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.76 (d, 2H), 7.41 (m, 2H), 7.26 (m, 2H), 7.21(d, 2H), 7.16 (d, 2H), 7.01 (m, 7H), 4.16 (t, 2H), 4.05 (t, 2H), 3.05(t, 2H), 2.97 (m, 6H), 2.18 (m, 2H), 1.24 (t, 6H) ppm

Example 429{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-cyclopropyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained from 20-30%EtOAc/hexane.

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of cyclopropanecarbonylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield: 260 mg).

MS m/z 544 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.65 (d, 2H), 7.31 (m, 4H), 7.21 (d, 2H), 7.18(s, 1H), 6.98 (d, 2H), 6.88 (d 2H), 4.18 (t, 2H), 4.08 (t, 2H), 3.07 (t,2H), 3.12 (m, 1H) 2.78 (m, 6H), 2.57 (m, 4H), 2.06 (m, 2H), 1.12 (t, 6H)ppm

Example 430{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-cyclopentyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained from 20-30%EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of cyclopentanecarbonylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield: 366 mg).

MS m/z 572 (M+H)⁺:

Example 431[3-(4-{4-[4-(biphenyl-4-yloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine(1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added,followed by a slow addition of the 2-bromo-1-(4-bromophenyl)ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold H₂O and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) wasadded, according to General Procedure R4. The reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate solution. Usualextractive work up with EtOAc gave the product imidazole, which waspurified by column chromatography (Silica gel). Pure product wasobtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution of theN-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine(0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol),followed by potassium carbonate (0.35 mmol) and 1,1′-biphenyl-4-ol (0.14mmol). The mixture was heated at 110° C. overnight, then diluted withH₂O (2 mL) and extracted with EtOAc (3×2 mL). The combined organicextract was dried over sodium sulfate, filtered and concentrated to anoil, which was purified by column chromatography (Silica gel). The pureproduct was obtained from 1-6% MeOH/DCM (yield 11 mg).

MS m/z 518 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.83-7.79 (m, 3H), 7.59-7.57 (m, 4H),7.45-7.43 (m, 4H), 7.42-7.34 (m, 4H), 7.11 (d, 2H), 7.05 (d, 3H), 4.10(t, 2H), 2.80-2.60 (m, 6H), 2.00-2.10 (m, 2H), 1.30 (t, 3H), 1.10 (t,3H) ppm.

Example 432diethyl-[3-(4-{4-[4-(3-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine(1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added,followed by a slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product was obtained from2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of1-(4-bromophenyl)-2-({-4-[3-(diethylamino)propoxy]phenyl}amino)ethanone(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) wasadded, according to General Procedure R4. The reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate solution. Usualextractive work up with EtOAc gave the product imidazole, which waspurified by column chromatography (Silica gel). Pure product wasobtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution ofN-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine(0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol),followed by potassium carbonate (0.35 mmol) and3-(trifluoromethyl)phenol (0.14 mmol). The mixture was heated at 110° C.overnight, then diluted with H₂O (2 mL) and extracted with EtOAc (3×2mL). The combined organic extract was dried over sodium sulfate,filtered and concentrated to an oil, which was purified by columnchromatography (Silica gel). The pure product was obtained from 1-6%MeOH/DCM (yield 10 mg).

MS m/z 510 (M+H)⁺:

Example 433[3-(4-{4-[4-(3,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine(1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added,followed by a slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product was obtained from2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) wasadded, according to General Procedure R4. The reaction mixture wasstirred at 90° C. overnight. The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate solution. Usualextractive work up with EtOAc gave the product imidazole, which waspurified by column chromatography (Silica gel). Pure product wasobtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution ofN-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine(0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol)followed by potassium carbonate (0.35 mmol), and 3,4-dichlorophenol(0.14 mmol). The mixture was heated at 110° C. overnight, then dilutedwith H₂O (2 mL) and extracted with EtOAc (3×2 mL). The combined organicextract was dried over sodium sulfate, filtered and concentrated to anoil, which was purified by column chromatography (Silica gel). The pureproduct was obtained from 1-6% MeOH/DCM (yield 15 mg).

MS m/z 510 (M+H)⁺:

Example 434[3-(4-{2-butyl-1-[4-(4-methoxy-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at rt for another hour (until the reaction was complete by HPLC).The solvent was removed and to this saturated aqueous sodium bicarbonatewas added. The product was extracted with EtOAc (3×) and washed withsodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and the1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flashchromatography (going by increasing gradient up to 10% MeOH in DCM). Theoverall yield was 60%.

4-Methoxyphenol (10 mmol) was dissolved in 15 ml of anhydrous DMF andpotassium carbonate (30 mmol) was added with stirring at rt.4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was thenheated under reflux at 80° C. for 18 h. The reaction was quenched with30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc(3×50 ml) and washed with sodium bicarbonate and water. The EtOAc layerwas dried over anhydrous sodium sulfate and filtered, after which thesolvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH(30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(4-methoxyphenoxy)aniline, which was used directly for furthertransformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-(4-methoxyphenoxy) aniline (1 eq, 2 mmol) inanhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by additionof the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone describedabove (2 mmol), according to General Procedure R2. The reaction mixturewas stirred under nitrogen at rt until completion, as indicated by TLCor HPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield 52%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 190mg).

MS m/z 529 (M+H)⁺:

¹H NMR (CDCl₃): δ7.7 (d, 2H), 7.2 (d, 2H), 7.16 (s, 1H), 6.8-7.1 (m,8H), 4.0 (t, 2H), 3.8 (s, 3H), 2.8-3.0 (m, 8H), 2.6 (m, 2H), 2.2 (m,2H), 1.6 (m, 2H), 1.2 (t, 6H), 0.8 (t, 3H) ppm.

Example 4351-[2-(4-{2-butyl-1-[4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-piperazine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added. The reaction mixture was stirred under nitrogen atrt until completion, as indicated by TLC. The mixture was diluted withEtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and driedwith magnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromoacetophenone was used for furthertransformation without further purification.

To a stirred solution of 4-(3-fluoro-4-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the alpha-bromoacetophenone described above (2 eq),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC and HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in Et₂O. The combined organic layers were washed with brine anddried over sodium sulfate. Evaporation of solvent in vacuuo afforded thedesired product. The crude alkylated aniline was purified bychromatography (Silica gel). Pure product was obtained from 5-20%EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by TLC and HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 5-15%EtOAc/Hexane (yield 80%).

(MS: m/z 562 (M+H)⁺)

The Above Product was Dissolved in MeOH (20 mL), and Pd/C (100 mg) wasAdded and the heterogeneous mixture was stirred overnight under hydrogenatmosphere using a balloon, according to General Procedure H. The Pd/Cwas removed by filtration. The solvent was removed in vacuuo, and thecrude phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

To a stirred solution of the phenol (0.16 mmol) obtained above inanhydrous DMF (5 mL) solid sodium hydride (60% dispersion in oil; 1.0mmol) was added in portions. After the addition,4-(2-methanesulfonyloxy)-piperazine-1-carboxylic acid tertbutylester(2.0 mmol) was added to the reaction mixture. The reaction mixture washeated at 90° C. overnight. After cooling the mix to rt, Et₂O (30 mL)was added to the reaction mixture followed by H₂O (10 mL). The organiclayer was washed with H₂O (2×15 mL) and brine, and dried over sodiumsulfate. The solvent was removed in vacuuo. Pure product was obtainedfrom 5-10% MeOH/DCM (yield ˜45%).

This product was dissolved in DCM (10 mL) and HCl (4.0 M in dioxane, 1.0mL) was added and stirrings continued overnight until reaction completedas indicated by HPLC. EtOAc (40 ml) added, followed by sodiumbicarbonate (sat, 15 mL). The organic layer was washed with brine (10mL) and dried with magnesium sulfate. The solvent was removed in invacuuo to give the title compound as white solid (yield 37 mg).

MS m/z 584 (M+H)⁺:

¹H NMR (CDCl₃): δ7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08 (d,2H), 6.92 (d, 2H), 4.05 (t, 2H), 3.0 (m, 4H), 2.8 (t, 2H), 3.4 (m, 6H),1.6 (m, 2H), 1.3 (m, 3H), 0.9 (t, 3H) ppm.

Example 436{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-dimethyl-amine

To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH (20 mL),1-bromo-4′-(4-chlorophenethoxy)acetophenone (4 mmol) was added at rt.The resulting mixture was then heated to reflux for 45 min. The reactionmixture was then cooled to rt and the solvent was removed in vacuuo. Theresulting solid was dissolved in EtOAc (30 mL), washed with H₂O (2×20mL) and brine (20 mL) and dried over sodium sulfate. Evaporation ofsolvent in vacuuo afforded the desired1-(4-hydroxyphenyl)amino-4′-(4-chlorophenethoxy)acetophenone, which wasused for further transformation.

The aminoacetophenone obtained as above (3 mmol) was dissolved in formicacid (3 mL) and added with ammonium formate (60 mmol). The resultingmixture was heated to 90° C. overnight. The reaction mixture was thencooled down and neutralized with saturated sodium bicarbonate solution.Usual extractive work up with EtOAc gave the product,4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H-imidazole,which was purified by column chromatography (Silica gel). Pure productwas obtained from 4-6% MeOH/DCM (yield ˜50%).

To a solution of the product obtained above (0.5 mmol) in anhydrous THF(2 mL), NaH (60% dispersion in oil; 1 mmol) was added at 0° C. Theresulting mixture was added with a solution of the mesylate ofN,N-dimethylpropanol (0.6 mmol) in THF (1 mL). The reaction mixture wasthen heated to 70° C. overnight. Usual extractive work up with EtOAcgave the product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained from 4-6% MeOH/DCM.

MS m/z 476 (M+H)⁺:

¹H NMR (CDCl₃): δ7.76 (s, 1H), 7.73 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H),7.25 (AB_(q), 4H), 6.99 (d, 2H), 6.92 (d, 2H,), 4.18 (t, 2H), 4.05 (t,2H), 3.07 (t, 2H), 2.49 (t, 2H), 2.28 (s, 6H), 1.99 (q, 2H) ppm.

Example 4374-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1H-imidazole

To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH (20 mL),1-bromo-4′-(4-chlorophenethoxy)acetophenone (4 mmol) was added at rt.The resulting mixture was then heated to reflux for 45 min. The reactionmixture was then cooled to rt and the solvent was removed in vacuuo. Theresulting solid was dissolved in EtOAc (30 mL), washed with H₂O (2×20mL) and brine (20 mL) and dried over sodium sulfate. Evaporation ofsolvent in vacuuo afforded the desired1-(4-hydroxyphenyl)amino-4′-(4-chlorophenethoxy)acetophenone, which wasused for further transformation.

The aminoacetophenone obtained as above (3 mmol) was dissolved in formicacid (3 mL) and added with ammonium formate (60 mmol). The resultingmixture was heated to 90° C. overnight. The reaction mixture was thencooled down and neutralized with saturated sodium bicarbonate solution.Usual extractive work up with EtOAc gave the product,4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H-imidazole,which was purified by column chromatography (Silica gel). Pure productwas obtained from 4-6% MeOH/DCM (yield ˜50%).

To a solution of the product obtained above (0.5 mmol) in anhydrous THF(2 mL), NaH (60% dispersion in oil; 1 mmol) was added at 0° C. Theresulting mixture was added with a solution of the mesylate of2-(N-methylpyrrolidin-2-yl)ethanol (0.6 mmol) in THF (1 mL). Thereaction mixture was then heated to 70° C. overnight. Usual extractivework up with EtOAc gave the product imidazole, which was purified bycolumn chromatography (Silica gel). Pure product was by obtained byelution with 4-6% MeOH/DCM (yield 125 mg).

MS m/z 503 (M+H)⁺:

¹H NMR (CDCl₃): δ7.75 (s, 1H), 7.72 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H),7.26 (AB_(q), 4H), 6.95 (d, 2H), 6.92 (d, 2H), 4.17 (t, 2H), 3.04 (t,2H), 2.90-2.50 (m, 4H), 2.43 (s, 3H), 2.30-1.50 (m, 7H) ppm.

Example 4381-{2-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}-piperazine

To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH (20 mL),1-bromo-4′-(4-chlorophenethoxy)acetophenone (4 mmol) was added at rt.The resulting mixture was then heated to reflux for 45 min. The reactionmixture was then cooled to rt and the solvent was removed in vacuuo. Theresulting solid was dissolved in EtOAc (30 mL), washed with H₂O (2×20mL) and brine (20 mL) and dried over sodium sulfate. Evaporation ofsolvent in vacuuo afforded the desired1-(4-hydroxyphenyl)amino-4′-(4-chlorophenethoxy)acetophenone, which wasused for further transformation.

The aminoacetophenone obtained as above (3 mmol) was dissolved in formicacid (3 mL) and added with ammonium formate (60 mmol). The resultingmixture was heated to 90° C. overnight. The reaction mixture was thencooled down and neutralized with saturated sodium bicarbonate solution.Usual extractive work up with EtOAc gave the product,4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H-imidazole,which was purified by column chromatography (Silica gel). Pure productwas obtained by elution with 4-6% MeOH/DCM (yield ˜50%).

To a solution of the product obtained above (0.5 mmol) in anhydrous THF(2 mL), NaH (60% dispersion in oil; 1 mmol) was added at 0° C. Theresulting mixture was added with a solution of the mesylate of1-(t-butyloxycarbonyl)-2-(2-hydroxy)ethylpiperazine (0.6 mmol) in THF (1mL). The reaction mixture was then heated to 70° C. overnight. Usualextractive work up with EtOAc gave the product imidazole, which waspurified by column chromatography (Silica gel). Pure product wasobtained by elution with 4-6% MeOH/DCM (yield ˜50%).

The product obtained above was treated with 4M HCl in dioxane (1 mL) andthe resulting mixture was stirred at rt for 4 h. Evaporation of thesolvent, repeated washing of the hydrochloride salt thus obtained withdiethyl ether and subsequent drying in vacuuo afforded the desiredproduct.

MS m/z 503 (M+H)⁺:

¹H NMR (CD₃OD): δ9.47 (s, 1H), 8.28 (s, 1H), 7.76 (d, 2H), 7.72 (d, 2H),7.33 (d, 2H), 7.29 (s, 4H), 7.06 (d, 2H), 4.58 (broad t, 2H), 4.22 (t,2H), 3.83 (broad t, 4H), 3.74 (broad t, 6H), 3.06 (t, 2H) ppm.

Example 439[3-(4-{2-(3-cyclohexyl-propyl)-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at it for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at it and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of 4-cyclohexylbutanoyl chloride (0.6 mmol,3 eq), according to General Procedure R3. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(overall yield: 60-70%) (yield 78 mg).

MS m/z 652 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 0.75-1.65 (m, 15H), 1.07 (t, 6H), 1.97 (m,2H), 2.62 (q, 4H), 2.63-2.70 (m, 4H), 4.02 (t, 2H), 6.90 (d, 2H), 7.07(d, 2H), 7.14 (s, 1H), 7.22 (br s, 1H), 7.23 (br d, 1H), 7.25 (d, 1H),7.31 (d, 2H), 7.69 (d, 2H) ppm.

Example 440diethyl-(3-{4-[1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-(3-phenoxy-propyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol),4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solidpotassium carbonate (60 mmol) was added, and the reaction mixture washeated to 90° C. for 5 h (monitored by TLC), according to GeneralProcedure L1. After cooling to rt, the reaction mixture was poured intocold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) andbrine (50 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo to afford the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct was used directly for further transformation without furtherpurification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (50 mg) untilcompletion as indicated by TLC or LC-MS, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directlyfor further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) andTEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwisemethanesulfonyl chloride (60 mmol), and the reaction mixture was stirredfor 2 h at 0° C. and followed by additional 1 h at rt. After the removalof the solvents in vacuuo, the crude mesylate was dissolved in DMF (100mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)were added, and the mixture was heated with stirring at 90° C. for 18 h(monitored by LC-MS). After cooling to rt, the reaction was quenchedwith cold H₂O (100 mL), and the resulting mixture was extracted withEtOAc (4×100 mL). The combined EtOAc extracts were washed with brine(3×60 ml), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred at rt for 1 h (monitored by LC-MS). The solvent was then removedin vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline(4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,followed by a slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4mmol), according to General Procedure R2. The reaction mixture wasstirred at rt and under nitrogen until completion (˜5 h), as indicatedby LC-MS. The reaction was quenched with saturated sodium bicarbonate(50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with brine (3×40 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuuo, andthe crude product was purified by silica gel column chromatographyeluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added,followed by a slow addition of 4-phenoxybutanoyl chloride (0.6 mmol, 3eq), according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for2-5 h (as monitored by LC-MS). The reaction mixture was then cooled downand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 mL), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(yield 73 mg).

MS m/z 662 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.06 (t, 6H), 1.97 (m, 2H), 2.24 (m, 2H), 2.60(q, 4H), 2.67 (t, 2H), 2.88 (t, 2H), 3.99 (t, 2H), 4.03 (t, 2H), 6.80(d, 2H), 6.90-7.25 (m, 8H), 7.01 (d, 2H), 7.15 (s, 1H), 7.28 (d, 1H),7.70 (d, 2H) ppm.

Example 441{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-methyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of acetyl chloride (2eq., 3.2 mmol), according to General Procedure R3. The reaction mixturewas stirred under nitrogen at 0° C. for 1 h and allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The reaction mixture wasthen diluted with cold water and the product was isolated in DCM. Thesolvent was removed in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 250 mg).

MS m/z 519 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.67 (d, 2H), 7.22 (d, 2H), 7.21 (m, 5H), 6.96(d, 2H), 6.84 (d, 2H), 4.17 (t, 2H), 4.07 (t, 2H), 3.06 (t, 2H), 2.78(t, 2H), 2.74 (m, 4H), 2.36 (s, 3H), 2.06 (m, 2H), 1.13 (t, 6H) ppm

Example 4423-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-1-ethyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at rt until completion, as indicatedby TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O(2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solventwas then removed in vacuuo to give a white solid. The1-[4-(benzyloxy)phenyl]-2-bromoethanone was used for furthertransformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone describedabove (2 eq), according to General Procedure R2. The reaction mixturewas stirred under nitrogen at rt until completion, as indicated by TLCand HPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in Et₂O. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired alkylated aniline, which was purified bychromatography (Silica gel). Pure product was obtained by elution with5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by TLC and HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with5-15% EtOAc/Hexane (yield 80%).

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) wasadded and the heterogeneous mixture was stirred overnight under hydrogenatmosphere using a balloon, according to General Procedure T2. The Pd/Cwas removed by filtration. The solvent was removed in vacuuo, and thecrude4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenolwas used for further transformation.

A stirred solution of the4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of1-(methylamino)piperidin-3-ol was then added to the reaction mixture,which was heated at 90° C. overnight, according to General Procedure T3.After cooling the mix to rt, Et₂O (30 mL) was added to the reactionmixture followed by H₂O (10 mL). The organic layer was washed with H₂O(2×15 mL) and brine, and dried over sodium sulfate. The solvent wasremoved in vacuuo. Pure imidazole was obtained by elution withchromatography in 5-10% MeOH/DCM (yield 52.0 mg).

MS m/z 583 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.7 (m, 2H), 7.3 (m, 3H), 7.24 (m, 2H), 7.13 (s, 1H),7.07 (d, 2H, J=8.8 Hz), 6.94 (m, 2H), 0.9-4.4 (m, 23H) ppm.

Example 443diethyl-[3-(4-{1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-methyl-1H-imidazol-4-yl}-phenoxy)-propyl]-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generatedby adding the corresponding alcohol to a 1M solution of potassiumt-butoxide in THF) was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. until completion, as indicated by TLC or HPLC. The solvent wasthen removed in vacuuo and the reaction mixture was treated with coldH₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof the solvent in vacuuo afforded the desired1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crudeproduct could be used directly for further transformation.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion, as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-[4-fluoro-3-(trifluoromethyl)phenoxy]aniline, which was used directlyfor further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylateof N,N-diethylaminopropanol (prepared from the corresponding alcohol andmethanesulfonyl chloride) (2.0 mmol) was added to the reaction mixtureand heated to 80° C. until completion according to General Procedure Q1,as indicated by TLC or HPLC. After cooling to rt, the reaction mixturewas diluted with water and the product was isolated in EtOAc. Thecombined organic layers were washed with saturated sodium bicarbonate(2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer wasdried over magnesium sulfate, and the solvent was removed in vacuuo toafford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. Thecrude alkylated product was purified using silica gel columnchromatography. Pure product was obtained with 2-3% MeOH/DCM. (yield50-60%)

To a stirred solution of the1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1 mmol)in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.,1.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo, the residue was treated with saturatedsodium bicarbonate and the product was isolated in EtOAc. The combinedorganic layers were washed with water (2×15 ml) and brine (15 ml). Theorganic layer was dried over magnesium sulfate, and the solvent wasremoved in vacuuo to afford the desired product. The crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of the 4-fluoro-3-trifluoromethyl-phenoxy aniline(1.2 eq., 1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3 mmol) wasadded, followed by slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(1.0 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followedby slow addition of acetyl chloride (2 eq., 2.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with water and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was purified using silica gel chromatography. Pure productwas obtained by elution with 3-4% MeOH/DCM (Yield 40-45%).

To a stirred solution of the amide described above (0.5 mmol) in aceticacid (1 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 108 mg).

MS m/z 542 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.33 (m, 5H), 7.18 (s, 1H), 7.09(d, 2H), 6.91 (d, 2H) 4.03 (t, 2H), 2.63 (m, 6H), 2.41 (s, 3H), 2.01 (m,2H), 1.08 (t, 6H) ppm

Example 444(3-{4-[4-(4-benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-(N,N-diethylaminopropoxy)aniline, which was used directly for furthertransformation without further purification.

To a stirred solution of the 4′-benzyloxyacetophenone (2 mmol) inanhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.,2.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the residue was treated with saturatedsodium bicarbonate. The aqueous layer was poured into EtOAc (20 mL) andthe product was isolated in EtOAc (2×20 mL). The combined organic layerswere washed with saturated sodium thiosulfate (2×10 mL), water (2×10 mL)and brine (15 mL). The organic layer was dried over magnesium sulfate,and the solvent was removed in vacuuo to afford the desired product. Thecrude alpha-bromoacetophenone was purified by chromatography (Silicagel). Pure product was obtained by elution with 20-30% EtOAc/hexane(yield ˜70-75%).

To a stirred solution of the 4-(N,N-diethylaminopropoxy)aniline (1.2eq., 2 mmol) in anhydrous DMF (5 mL) the alpha-bromoacetophenone (1.6mmol) described above was added slowly, according to General ProcedureR2. The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by TLC or HPLC. The reaction mixture was thendiluted with cold water and the product was isolated in EtOAc. Thecombined organic layers were washed with brine and dried over sodiumsulfate. Evaporation of solvent in vacuuo afforded the desired product.The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.6 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followedby slow addition of valeryl chloride (2 eq., 3.2 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with cold waterand the product was isolated in DCM. The solvent was removed in vacuuo,and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield 179 mg).

MS m/z 512 (M+H)⁺:

¹H NMR (CDCl₃): δ7.69 (d, 2H), 7.15-7.50 (m, 8H), 7.09 (s, 1H), 6.96 (m,3H), 5.05 (s, 2H), 4.12 (t, 2H), 3.21 (broad m, 2H), 3.15 (q, 4H), 2.64(t, 2H) 2.38 (broad m, 2H), 1.60 (q, 2H) 1.41 (t, 6H) 1.20-1.35 (m, 2H),0.81 (t, 6H) ppm.

Example 445[3-(4-{2-butyl-1-[4-(2,5-difluoro-benzyloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at rt for another hour (until the reaction was complete by HPLC).The solvent was removed and saturated aqueous sodium bicarbonate wasadded. The product was extracted with EtOAc (3×) and washed with sodiumbicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and theproduct 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified byflash chromatography (going by increasing gradient up to 10% MeOH inDCM). The overall yield was 60%.

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (6 mL) at 0° C., a 1M solution of a potassium alkoxide (2.2 mmol) inTHF (may be generated by adding the 2,5-difluorobenzyl alcohol to a 1Msolution of KOBu^(t) in THF) was added dropwise and under a nitrogenstream, according to General Procedure L1. The reaction mixture wasstirred at 0° C. until completion, as indicated by TLC or HPLC. Thereaction mixture was then treated with cold H₂O (15 mL), and extractedwith EtOAc (2×15 mL). The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of the solvent in vacuuoafforded the desired 4-alkoxynitrobenzene. The crude product could beused directly for further transformation without any purification, orafter purifying using silica gel column chromatography.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (6mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion, as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(2,5-difluoro-benzyloxy)aniline, which was used directly for furthertransformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-(2,5-difluoro-benzyloxy)aniline (1 eq, 2 mmol) inanhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by additionof the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone describedabove (2 mmol), according to General Procedure R2. The reaction mixturewas stirred under nitrogen at rt until completion, as indicated by TLCor HPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product by elution with2-4% MeOH/DCM (yield 50%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 mmol, 20 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield 208 mg).

MS m/z 549 (M+H)⁺:

¹H NMR (CDCl₃): δ7.68 (d, 2H), 7.24 (m, 5H), 7.13 (s, 1H), 7.06 (d, 2H),6.89 (d, 2H), 5.17 (s, 2H), 4.02 (t, 2H), 2.62-2.78 (m, 8H), 1.98 (m,2H), 1.60 (m, 2H), 1.27 (m, 2H), 1.11 (t, 6H), 0.82 (t, 3H) ppm.

Example 4463-(S)-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxymethyl)-1-ethyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added. The reaction mixture was stirred under nitrogen atrt until completion, as indicated by TLC. The mixture was diluted withEtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and driedwith magnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromoacetophenone was used for furthertransformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the alpha-bromoacetophenone described above (2 eq),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC and HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in Et₂O. The combined organic layers were washed with brine anddried over sodium sulfate. Evaporation of solvent in vacuuo afforded thedesired product. The crude alkylated aniline was purified bychromatography (Silica gel). Pure product was obtained by elution with5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by TLC and HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with5-15 EtOAc/Hexane (yield 80%).

(MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) wasadded and the heterogeneous mixture was stirred overnight under hydrogenatmosphere using a balloon, according to General Procedure T2. The Pd/Cwas removed by filtration. The solvent was removed in vacuuo, and thecrude4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol(MS: m/z 472 (M+H)⁺) was used for further transformation.

A stirred solution of the4-(1-{-4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of[(3S)-1-ethylpiperidin-3-yl]methanol (1.5-2.0 eq) was added to thereaction mixture, which was heated at 90° C. overnight, according toGeneral Procedure T3. After cooling the mix to rt, Et₂O (30 mL) wasadded to the reaction mixture followed by H₂O (10 mL). The organic layerwas washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate.The solvent was removed in vacuuo. Pure imidazole was obtained byelution with chromatography in 5-10% MeOH/DCM (yield 50.0 mg).

MS m/z 597 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08(d, 2H), 6.92 (d, 2H), 4.05 (m, 1H), 3.92 (m, 2H), 2.60 (m, 4H), 1.0-2.5(m, 18H) ppm.

Example 447(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(2,4,4-trimethyl-pentyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of 3,5,5-trimethylhexanoyl chloride (2 eq., 3.2 mmol), according to General Procedure R3.The reaction mixture was stirred under nitrogen at 0° C. for 1 h andallowed to warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 296 mg).

MS m/z value (M+H)⁺: 617

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.22 (d, 2H), 7.21 (m, 5H), 6.96(d, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.07 (t, 2H), 3.09 (t, 2H), 2.88(d, 2H), 2.79 (m, 6H), 2.05 (m, 3H), 1.11 (t, 6H), 0.97 (d, 2H), 0.87(d, 3H), 0.78 (s, 9H) ppm

Example 4483-(R)-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxymethyl)-1-ethyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrousDCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide(1.1 eq.) was added. The reaction mixture was stirred under nitrogen atrt until completion, as indicated by TLC. The mixture was diluted withEtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and driedwith magnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromoacetophenone was used for furthertransformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline(1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed byslow addition of the alpha-bromoacetophenone described above (2 eq),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC and HPLC. Thereaction mixture was then diluted with cold H₂O and the product wasisolated in Et₂O. The combined organic layers were washed with brine anddried over sodium sulfate. Evaporation of solvent in vacuuo afforded thedesired product. The crude alkylated aniline was purified bychromatography (Silica gel). Pure product was obtained by elution with5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followedby slow addition of valeryl chloride (3 eq, 3.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by TLC and HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with5-15% EtOAc/Hexane (yield 80%). (MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) wasadded and the heterogeneous mixture was stirred overnight under hydrogenatmosphere using a balloon, according to General Procedure T2. The Pd/Cwas removed by filtration. The solvent was removed in vacuuo, and thecrude4-(1-{-4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol(MS: m/z 472 (M+H)⁺) was used for further transformation.

A stirred solution of the4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of[(3R)-1-ethylpiperidin-3-yl]methanol (1.5-2.0 eq) was added to thereaction mixture, which was heated at 90° C. overnight, according toGeneral Procedure T3. After cooling the mix to rt, Et₂O (30 mL) wasadded to the reaction mixture followed by H₂O (10 mL). The organic layerwas washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate.The solvent was removed in vacuuo. Pure imidazole was obtained byelution with chromatography in 5-10% MeOH/DCM (yield 50.0 mg).

MS m/z 597 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08(d, 2H,), 6.92 (d, 2H), 4.05 (m, 1H), 3.92 (m, 2H), 2.60 (m, 4H),1.0-2.5 (m, 18H). ppm.

Example 449[3-(4-{2-butyl-1-[4-(3-tert-butyl-phenoxy)-phenyl]1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at rt for another hour (until the reaction was complete by HPLC).The solvent was removed and saturated aqueous sodium bicarbonate wasadded. The product was extracted with EtOAc (3×) and washed with sodiumbicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and theproduct 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified byflash chromatography (going by increasing gradient up to 10% MeOH inDCM). The overall yield was 60%.

4-Methoxyphenol (10 mmol) was dissolved in 15 ml of anhydrous DMF andpotassium carbonate (30 mmol) was added with stirring at rt.4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was thenheated under reflux at 80° C. for 18 h. The reaction was quenched with30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc(3×50 ml) and washed with sodium bicarbonate and water. The EtOAc layerwas dried over anhydrous sodium sulfate and filtered, after which thesolvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH(30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion as indicated by TLC or HPLC, according to General ProcedureH. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(3-tert-butyl-phenoxy)aniline, which was used directly for furthertransformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-(3-tert-butyl-phenoxy)aniline (1 eq, 2 mmol) inanhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by additionof the 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone describedabove (2 mmol), according to General Procedure R2. The reaction mixturewas stirred under nitrogen at rt until completion, as indicated by TLCor HPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product by elution with2-4% MeOH/DCM (yield 51%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM(yield 177 mg).

MS m/z 555 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.3 (m, 4H), 7.1-7.2 (m, 5H),6.9 (d, 2H), 4.0 (t, 2H), 2.8-3.0 (m, 8H), 2.0 (m, 2H), 1.6 (m, 2H), 1.4(m, 2H), 1.2 (15H), 0.8 (t, 3H) ppm

Example 450{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-methoxymethyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of methoxy acetylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 265 mg).

MS m/z 549 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.72 (d, 2H), 7.37 (d, 2H), 7.48 (m, 5H), 6.98(d, 2H), 6.85 (d, 2H), 4.41 (s, 2H), 4.18 (t, 2H), 4.07 (t, 2H), 3.45(s, 3H), 3.06 (t, 2H), 2.86 (m, 6H), 2.08 (m, 2H), 1.17 (t, 6H) ppm

Example 451(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(1-ethyl-propyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of 2-ethyl butyrylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 230 mg).

MS m/z 575 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.71 (d, 2H), 7.27 (m, 6H), 7.06 (s, 1H), 6.95(d, 2H), 6.87 (d, 2H), 4.09 (t, 2H), 4.02 (t, 2H), 3.07 (t, 2H), 2.72(m, 6H), 2.49 (m, 1H), 2.06 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H), 1.08(t, 6H), 0.96 (t, 3H), 0.88 (t, 3H) ppm

Example 452(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(3-phenoxy-propyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of 4-phenoxy butyrylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 250 mg).

MS m/z 638 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.23-7.25 (m, 8H), 7.12 (s, 1H),6.92 (m 5H), 6.81 (d, 2H), 4.18 (t, 2H), 4.09 (t, 2H), 3.95 (t, 2H),3.07 (t, 2H), 2.85 (m, 8H), 2.22 (m, 2H), 2.05 (m, 2H), 1.20 (t, 6H) ppm

Example 453(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(1-propyl-butyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of 2-N-propyl-N-valerylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 288 mg).

MS m/z 602 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.23-7.25 (m, 6H), 7.04 (s, 1H),6.97 (d, 2H), 6.87 (d, 2H), 4.18 (t, 2H), 4.09 (t, 2H), 3.06 (t, 2H),2.87 (m, 6H), 2.63 (m, 1H), 2.13 (m, 2H), 1.81 (m, 2H), 1.54 (m, 2H),1.17 (t, 10H), 0.89 (t, 6H) ppm

Example 454{3-[4-(2-(4-chloro-phenoxymethyl)-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of 4-chlorophenoxy acetylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, -20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 250 mg).

MS m/z 644 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.72 (d, 2H), 7.36 (d, 2H), 7.23-7.25 (m, 4H),7.23 (m, 4H), 6.91 (m, 5H), 4.95 (s, 2H), 4.17 (t, 2H), 4.05 (t, 2H),3.07 (m, 8H), 2.21 (m, 2H), 1.27 (t, 6H) ppm

Example 455{3-[4-(2-benzyloxymethyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of benzyloxyacetylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to it until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield: 350 mg).

MS m/z 624 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.71 (d, 2H), 7.68 (d, 2H), 7.31 (m, 7H), 7.25(d, 2H), 7.21 (s, 1H), 6.94 (d, 2H), 6.89 (d, 2H), 4.58 (s, 2H), 4.49(s, 2H), 4.15 (t, 2H), 4.08 (t, 2H), 3.11 (t, 2H), 2.89 (m, 6H), 2.18(m, 2H), 1.35 (t, 6H) ppm

Example 456{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-5-methyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-propan-1-one (1.0 mmol) indioxane (10.0 mL) at rt, pyridinium bromide perbromide (1.1 eq) wasadded. The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by TLC. The mixture was diluted with EtOAc (100ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried withmagnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromoketone was used for further transformationwithout further purification.

A solution of the above alpha-bromoketone (1.0 eq),N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA (1.5eq) in anhydrous DMF (10 mL) was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. The solventwas removed in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained by elution with 2-7% MeOH/DCM (yield ˜55%).

To a stirred solution of alkylated aniline described above (0.55 mmol)in anhydrous THF (5 mL) at 0° C., TEA (3.0 mmol) was added, followed byslow addition of isovaleryl chloride (5.0 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to ambient temperature until completion, asindicated by HPLC. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (0.55 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole (yield 190 mg).

MS m/z 574 (M+H)⁺:

Example 457{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-2-isobutyl-5-propyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-pentan-1-one (1.0 mmol) indioxane (10.0 mL) at rt , pyridinium bromide perbromide (1.1 eq.) wasadded. The reaction mixture was stirred under nitrogen at it untilcompletion, as indicated by TLC. The mixture was diluted with EtOAc (100ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried withmagnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromophenone was used for further transformation.

A solution of the above alpha-bromophenone (1.0 eq),N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA (1.5eq) in anhydrous DMF (10 mL) was stirred under nitrogen at it untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. The solventwas removed in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained by elution with 2-5% MeOH/DCM (yield ˜50%).

To a stirred solution of alkylated aniline described above (0.48 mmol)in anhydrous THF (5 mL) at 0° C., DMAP (0.25 eq) was added, followed byslow addition of isovaleryl chloride (5.0 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to ambient temperature until completion, asindicated by HPLC. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (0.48 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole (yield 180 mg).

MS m/z 602 (M+H)⁺:

¹H NMR (CDCl₃): δ7.58 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.11 (d, 2H),6.98 (d, 2H), 6.91 (d, 2H), 4.17 (t, 2H), 4.08 (t, 2H), 3.07 (t, 2H),2.6 (t, 2H), 2.57 (q, 6H), 2.47 (t, 4H), 2.36 (d, 2H), 2.0 (m, 3H), 1.3(m, 2H), 1.05 (t, 6H), 0.82 (d, 6H), 0.72 (t, 3, H) ppm.

Example 458{3-[4-(5-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-hexan-1-one (0.785 mmol) indioxane (10.0 mL) at rt, pyridinium bromide perbromide (1.1 eq) wasadded. The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by TLC. The mixture was diluted with EtOAc (100ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried withmagnesium sulfate. The solvent was then removed in vacuuo to give awhite solid. The alpha-bromophenone was used for further transformation.

A solution of the above alpha-bromophenone (1.0 eq),N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA (1.5eq) in anhydrous DMF (10 mL) was stirred under nitrogen at rt for 24hour. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in Et₂O. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product was obtained byelution with 2-7% MeOH/DCM (yield ˜47%).

To a stirred solution of alkylated aniline described above (0.31 mmol)in anhydrous THF (5 mL) at 0° C., DMAP (0.25 eq) was added, followed byslow addition of isovaleryl chloride (5.0 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to ambient temperature until completion, asindicated by HPLC. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (0.31 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole (yield 108 mg).

MS m/z 616 (M+H)⁺:

¹H NMR (CDCl₃): δ7.6 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.11 (d, 2H),7.00 (d, 2H), 6.90 (d, 2H), 4.18 (t, 2H), 4.08 (t, 2H, 3.06 (t, 2H),2.45-2.65 (m, 8H), 2.36 (d, 2H), 2.0 (m, 4H), 0.7-1.3 (m, 18H) ppm.

Example 459{4-{4-{2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-[4-(3-diethylamino-propoxy)-phenyl]-1H-imidazol-2-yl}-MeOH

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrousTHF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide(2.2 mmol) in THF was added dropwise and under a nitrogen stream,according to General Procedure L1. The reaction mixture was stirred at0° C. for 1 h and allowed to warm to it until completion, as indicatedby TLC or HPLC. The reaction mixture was then treated with cold H₂O (15mL), and extracted with EtOAc (2×15 mL). The combined organic layerswere washed with brine and dried over sodium sulfate. Evaporation of thesolvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crudeproduct was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtainedabove was dissolved in MeOH (10 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desired4-alkoxyaniline, which was used directly for further transformationwithout further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL)at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethylmesylate (2.0 mmol) was added to the reaction mixture and heated to 80°C. until completion according to General Procedure Q1, as indicated byTLC or HPLC. After cooling to rt, the reaction mixture was quenchedusing cold water (20 ml) and the product was isolated in EtOAc (2×20ml). The combined organic layers were washed with saturated sodiumbicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedacetophenone was used for further transformation.

To a stirred solution of the1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrousMeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)was added, according to General Procedure R1. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and was allowed to warm to ituntil completion, as indicated by TLC or HPLC. The solvent was thenremoved in vacuuo and the residue was treated with saturated sodiumbicarbonate. The aqueous layer was poured into EtOAc (20 ml) and theproduct was isolated in EtOAc (2×20 ml). The combined organic layerswere washed with saturated sodium bicarbonate (2×10 ml), and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified bychromatography (Silica gel). Pure product was obtained by elution with20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of theN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (1.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold water and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation.

To a stirred solution of1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanonedescribed above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,4.8 mmol) was added, followed by slow addition of benzyloxyacetylchloride (2 eq., 3.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to it until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in DCM. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in aceticacid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to it and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained by elution with4-6% MeOH/DCM (yield 30-40%).

To a stirred solution of the pure imidazole (0.48 mmol) described above6N HCl was added and the reaction mixture was refluxed overnight. Thereaction mixture was then cooled to it and neutralized with 3N sodiumhydroxide solution. Usual extractive work up with EtOAc gave the productimidazole, which was purified by column chromatography (Silica gel).Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 130 mg).

MS m/z 534 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.66 (d, 2H), 7.41 (d, 2H), 7.28 (d, 2H), 7.22(m, 3H), 6.99 (d, 2H), 6.89 (d, 2H), 4.62 (s, 2H), 4.17 (t, 2H), 4.08(t, 2H), 3.07 (t, 2H), 2.88 (m, 6H), 2.18 (m, 2H), 1.24 (t, 6H) ppm

Example 460diethyl-[3-(4-{2-isobutyl-4-[4-(4-phenoxy-benzyloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained by elution with 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

A stirred solution of the4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) obtained above in anhydrous DMF (5.0 mL) was treated with solidsodium hydride (60% dispersion in oil; 1.0 mmol) in portions. Themesylate of (4-phenoxyphenyl)methanol (1.1 eq) was added to the reactionmixture, which was stirred at rt overnight, according to GeneralProcedure T3. Et₂O (30 mL) was added to the reaction mixture followed byH₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine,and dried over sodium sulfate. The solvent was removed in vacuuo. Pureimidazole was obtained by elution with chromatography in 5-10% MeOH/DCM(yield 70.0 mg).

MS m/z 604 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H) 6.9-7.4 (m, 16H), 5.0 (s, 2H), 4.1 (t,2H), 3.0 (m, 6H), 2.52 (d), 2.26 (m, 2H), 2.01 (m, 1H), 1.31 (t, 6H),0.84 (d, 6H) ppm.

Example 461[3-(4-{4-[4-(4-benzyloxy-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained by elution with 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

A stirred solution of4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of[4-(benzyloxy)phenyl]methanol (1.1 eq) was added to the reactionmixture, and stirred at rt overnight, according to General Procedure T3.Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL).The organic layer was washed with H₂O (2×15 mL) and brine, and driedover sodium sulfate. The solvent was removed in vacuuo. Pure imidazolewas obtained from chromatography with 5-10% MeOH/DCM (yield 70.0 mg).

MS m/z 618 (M+H)⁺:

¹H NMR (CDCl₃): δ7.70 (d, 2H), 7.3-7.45 (m, 7H), 7.21 (d, 2H), 7.1 (s,1H), 6.9 (m, 6H), 5.07 (s, 2H), 5.00 (s, 2H), 4.1 (t, 2H), 3.0 (m, 6H),2.52 (d, 2H), 2.26 (m, 2H), 2.01 (m, 1H), 1.31 (t, 6H), 0.84 (d, 6H)ppm.

Example 462[3-(4-{4-[4-(2-benzenesulfonylmethyl-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained by elution with 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

A stirred solution of4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of{2-[(phenylsulfonyl)methyl]phenyl}methanol (1.1 eq) was added to thereaction mixture, and stirred at rt overnight, according to GeneralProcedure T3. Et₂O (30 mL) was added to the reaction mixture followed byH₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine,and dried over sodium sulfate. The solvent was removed in vacuuo. Pureimidazole was obtained from chromatography with 5-10% MeOH/DCM (yield 77mg).

MS m/z 666 (M+H)⁺:

¹H NMR (CDCl₃): δ7.6-7.73 (m, 6), 7.3-7.5 (m, 4H), 7.20 (d, 2H), 7.1 (m,2H), 6.97 (d, 2H), 6.9 (d, 2H), 4.93 (s, 2H), 4.5 (s, 2H), 4.07 (t, 2H),2.6 (t, 2H), 2.63 (q, 4H), 2.53 (d, 2H), 2.01 (m, 3H), 1.08 (t, 6H),0.85 (d, 6H) ppm.

Example 463diethyl-[3-(4-{2-isobutyl-4-[4-(3,4,5-trimethoxy-benzyloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

A stirred solution of4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of(3,4,5-trimethoxyphenyl)methanol (1.1 eq) was added to the reactionmixture, and stirred at rt overnight, according to General Procedure T3.Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL).The organic layer was washed with H₂O (2×15 mL) and brine, and driedover sodium sulfate. The solvent was removed in vacuuo. Pure imidazolewas obtained from chromatography with 5-10% MeOH/DCM (yield 66 mg).

MS m/z 602 (M+H)⁺:

¹H NMR (CDCl₃): δ7.71 (d, 2H), 7.21 (d, 2H), 6.97 (m, 4H), 6.66 (s, 1H),5 (s, 2H), 4.1 (t, 2H), 3.86 (s, 6H), 3.82 (s, 3H), 3.0 (m, 6H), 2.51(d, 2H), 2.25 (m, 2H), 2.01 (m, 1H), 1.3 (t, 6H), 0.84 (d, 6H) ppm.

Example 464[3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(5.2 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 6.2 mmol) was added slowly in small portions,according to General Procedure R1. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and was allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was then removed invacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followedby slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(5.2 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was extracted in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield ˜22%).

To a stirred solution of alkylated 4-amino-4′-chlorodiphenyl etherdescribed above (0.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,1.2 mmol) was added, followed by slow addition of isovaleryl chloride (3eq., 1.2 mmol), according to General Procedure R3. The reaction mixturewas stirred under nitrogen at 0° C. for 1 h and allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was removedin vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone(0.4 mmol) obtained as above in acetic acid (3 mL), solid ammoniumacetate (8 mmol) was added in one portion, according to GeneralProcedure R4. The reaction mixture was then heated to 100° C. overnight.The reaction mixture was cooled to rt, and treated with saturatedaqueous sodium bicarbonate solution while stirring to until the pH was7-8. The contents were extracted with EtOAc (2×15 mL). The combinedorganic layers was washed with H₂O (2×15 mL) and brine, and dried oversodium sulfate. Evaporation of the solvent in vacuuo afforded thedesired N-aryl imidazole. The crude product was purified using silicagel column chromatography (2-5% MeOH/DCM) (yield 117 mg).

MS m/z 532 (M+H)⁺:

¹H NMR (CDCl₃): δ7.63 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.06 (s, 1H),7.01 (d, 2H), 6.98 (d, 2H), 6.83 (d, 2H), 3.99 (t, 2H), 2.79 (t, 2H),2.72 (q, 4H), 2.49 (d, 2H), 2.30-1.90 (m, 3H), 1.10 (t, 6H), 0.80 (d,6H) ppm.

Example 465[3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-(2-cyclopentyl-ethyl)-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(5.2 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 6.2) was added slowly in small portions,according to General Procedure R1. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and was allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was then removed invacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followedby slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(5.2 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was extracted in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield ˜22%).

To a stirred solution of alkylated 4-amino-4′-chlorodiphenyl etherdescribed above (0.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,1.2 mmol) was added, followed by slow addition of 3-cyclopentylpropionylchloride (3 eq., 1.2 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. The solventwas removed in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone(0.4 mmol) obtained as above in acetic acid (3 mL), solid ammoniumacetate (8 mmol) was added in one portion, according to GeneralProcedure R4. The reaction mixture was then heated to 100° C. overnight.The reaction mixture was cooled to rt, and treated with saturatedaqueous sodium bicarbonate solution while stirring to until the pH was7-8. The contents were extracted with EtOAc (2×15 mL). The combinedorganic layers was washed with H₂O (2×15 mL) and brine, and dried oversodium sulfate. Evaporation of the solvent in vacuuo afforded thedesired N-aryl imidazole. The crude product was purified using silicagel column chromatography (2-5% MeOH/DCM) (yield 180 mg).

MS m/z 572 (M+H)⁺:

¹H NMR (CDCl₃): δ7.69 (d, 2H), 7.35 (d, 2H), 7.29 (d, 2H), 7.14 (s, 1H),7.08 (d, 2H), 7.02 (d, 2H), 6.89 (d, 2H), 4.05 (t, 2H), 2.95 (t, 2H)2.85 (q, 4H), 2.71-2.65 (m, 2H), 2.19-2.12 (m, 3H), 1.72-1.61 (m, 4H),1.59-1.42 (m, 4H), 1.21 (t, 6H), 1.01 (m, 2H) ppm.

Example 466[3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-phenethyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(5.2 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 6.2) was added slowly in small portions,according to General Procedure R1. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and was allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was then removed invacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followedby slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(5.2 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was extracted in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield ˜22%).

To a stirred solution of the alkylated 4-chloroalkoxy aniline describedabove (0.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 1.2 mmol)was added, followed by slow addition of hydrocinnamoyl chloride (3 eq.,1.2 mmol), according to General Procedure R3. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone(˜0.4 mmol) obtained as above in acetic acid (3 mL), solid ammoniumacetate (8 mmol) was added in one portion, according to GeneralProcedure R4. The reaction mixture was then heated to 100° C. overnight.The reaction mixture was cooled to rt, and treated with saturatedaqueous sodium bicarbonate solution while stirring to until the pH was7-8. The contents were extracted with EtOAc (2×15 mL). The combinedorganic layers was washed with H₂O (2×15 mL) and brine, and dried oversodium sulfate. Evaporation of the solvent in vacuuo afforded thedesired N-aryl imidazole. The crude product was purified using silicagel column chromatography (2-4% MeOH/DCM) (yield 50 mg).

MS m/z 580 (M+H)⁺:

¹H NMR (CDCl₃): δ8.41 (m, 2H), 7.92 (m, 2H), 7.62 (d, 2H, 7.33 (d, 2H),7.25-7.21 (m, 2H), 7.13-7.08 (m, 1H), 7.04 (s, 1H), 6.98 (m, 2H), 6.92(m, 2H), 6.75 (m, 2H), 4.05 (t, 2H), 3.31 (m, 2H), 3.26-3.05 (m, 6H),2.35 (m, 2H), 1.40 (t, 6H), 1.21 (m, 2H) ppm.

Example 467[3-(4-{2-(4-tert-butyl-phenoxymethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at rt for another hour (until the reaction was complete by HPLC).The solvent was removed and to this saturated aqueous sodium bicarbonatewas added. The product was extracted with EtOAc (3×) and washed withsodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and theproduct 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified byflash chromatography (going by increasing gradient up to 10% MeOH inDCM). The overall yield was 60%.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(5 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-chlorophenoxy aniline (1 eq, 5 mmol) in anhydrous DMF(10 mL), DIEA (3 eq 15 mmol) was added, followed by addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield 52%).

To a solution of2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanonedescribed above (2 mmol) in anhydrous DCM (5 mL), PS-carbodimide (2 eq,4 mmol) and 4-t-butylphenoxy-acetic acid (3 mmol) were added. Thereaction mixture was shaken overnight and next day filtered to give thedesired amide. The crude amide was used for further transformation.

To a stirred solution of the amide described above (2 mmol) in aceticacid (8 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 255mg).

MS m/z 638 (M+H)⁺:

¹H NMR (CDCl₃): δ7.72 (d, 2H), 7.44 (d, 2H), 7.28-7.35 (m, 5H), 6.8-7.1(m, 8H), 5.01 (s, 2H), 4.06 (t, 2H), 3.13-3.24 (m, 6H), 2.28 (m, 2H),1.23-1.38 (m, 15H) ppm.

Example 468[3-(4-{2-butyl-1-[4-(2,4-dichloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 2,4-dichlorophenol (10 mmol) to the reaction mixture andheating to 80° C. until the reaction was complete as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was poured into H₂O (100ml), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 ml) and brine(50 ml), and dried over sodium sulfate. The solvent was removed invacuuo to afford the desired 4-(2,4-dichloro-phenoxy)-1-nitrobenzene.The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in MeOH(20 mL), and treated with SnCl₂.2H₂O (50 mmol), according to GeneralProcedure I. The reaction mixture was heated under reflux untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. Theresidue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueousNaOH (50 mL), brine (50 mL) and dried over sodium sulfate. The solventwas removed in vacuuo to afford the desired4-(2,4-dichloro-phenoxy)aniline, which was used directly for furthertransformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4.4 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 5.3 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-(2,4-dichloro-phenoxy)aniline described above(1.2 eq., 5.2 mmol) in anhydrous DMF (20 mL) DIEA (3 eq. 15 mmol) wasadded, followed by slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(4.4 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield ˜5%).

To a stirred solution of alkylated 4-(2,4-dichloro-phenoxy)anilinedescribed above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,0.6 mmol) was added, followed by slow addition of valeryl chloride (3eq., 0.6 mmol), according to General Procedure R3. The reaction mixturewas stirred under nitrogen at 0° C. for 1 h and allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was removedin vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (0.2 mmol) obtained asabove in acetic acid (3 mL), solid ammonium acetate (6 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM).

MS m/z 566 (M+H)⁺:

¹H NMR (CDCl₃): δ7.96 (s, 1H), 7.87 (m, 2H), 7.64 (d, 2H), 7.42 (m, 2H),7.30 (d, 2H), 7.15 (s, 1H), 6.94-6.84 (m, 2H), 4.12 (m, 2H), 3.71-3.42(m, 6H), 3.14 (m, 2H), 2.29 (t, 2H), 1.59-1.50 (m, 2H), 1.41-1.32 (m,2H), 1.31 (t, 6H), 0.85 (m, 3H) ppm.

Example 469[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-methyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the1-[4-(3-diethylamino-propoxy)-phenyl]-propane-1-one (1.08 mmol) inanhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added,according to General Procedure R1. The reaction mixture was heated underreflux overnight. The solvent was then removed in vacuuo and the crudealpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq),4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0eq) was added. The reaction mixture was stirred under nitrogen at 90° C.until completion, as indicated by HPLC. The reaction mixture was cooledto rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate(10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesiumsulfate. Evaporation of solvent in vacuuo gave a crude oil. The crudealkylated aniline was purified by chromatography (Silica gel). Pureproduct was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) inanhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed byslow addition of valeryl chloride (5.0 eq), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to ambient temperature until completion, asindicated by HPLC. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield 66 mg).

MS m/z 546 (M+H)⁺:

¹H NMR (CDCl₃): δ7.59 (d, 2H), 7.35 (d, 2H), 7.19 (d, 2H), 7.08 (d, 2H),7.03 (d, 2H), 6.93 (d, 2H), 4.02 (t, 2H), 2.51-2.64 (m, 8H), 2.13 (s,3H), 1.94 (m, 2H), 1.58 (m, 2H), 1.27 (m, 2H), 1.04 (t, 6H), 0.82 (t,3H) ppm.

Example 470[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-propyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the1-[4-(3-diethylamino-propoxy)-phenyl]-pentane-1-one (1.08 mmol) inanhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added,according to General Procedure R1. The reaction mixture was heated underreflux overnight. The solvent was then removed in vacuuo and the crudealpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq),4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0eq) was added. The reaction mixture was stirred under nitrogen at 90° C.until completion, as indicated by HPLC. The reaction mixture was cooledto rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate(10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesiumsulfate. Evaporation of solvent in vacuuo gave a crude oil. The crudealkylated aniline was purified by chromatography (Silica gel). Pureproduct was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) inanhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed byslow addition of valeryl chloride (5.0 eq), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to ambient temperature until completion, asindicated by HPLC. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield 73 mg).

MS m/z 574 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.50 (d, 2H), 7.34 (d, 2H), 7.20 (d, 2H), 7.07 (d,2H), 7.02 (d, 2H), 6.87 (d, 2H), 4.07 (t, 2H), 3.1-3.2 (m, 6H), 2.40-2.6(m, 4H), 2.2 (m, 2H), 1.2-1.4 (m, 12H), 0.79 (t, 3H), 0.72 (t, 3H) ppm.

Example 471[3-(4-{2,5-dibutyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the1-[4-(3-diethylamino-propoxy)-phenyl]-hexanane-1-one (1.08 mmol) inanhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added,according to General Procedure R1. The reaction mixture was heated underreflux overnight. The solvent was then removed in vacuuo and the crudealpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq),4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0eq) was added. The reaction mixture was stirred under nitrogen at 90° C.until completion, as indicated by HPLC. The reaction mixture was cooledto rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate(10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesiumsulfate. Evaporation of solvent in vacuuo gave a crude oil. The crudealkylated aniline was purified by chromatography (Silica gel). Pureproduct was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) inanhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed byslow addition of valeryl chloride (5.0 eq), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to ambient temperature until completion, asindicated by HPLC. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield 67.0 mg).

MS m/z 588 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.54 (d, 2H), 7.36 (d, 2H), 7.24 (d, 2H), 7.09 (d,2H), 7.03 (d, 2H), 6.90 (d, 2H), 4.07 (t, 2H), 3.2-3.3 (m, 6H), 2.45-2.6(m, 4H), 2.2 (m, 2H), 1.1-1.6 (m, 14H), 0.8 (t, 3H), 0.70 (t, 3H) ppm.

Example 472[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-ethyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the1-[4-(3-diethylamino-propoxy)-phenyl]-butane-1-one (1.08 mmol) inanhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added,according to General Procedure R1. The reaction mixture was heated underreflux overnight. The solvent was then removed in vacuuo and the crudealpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq),4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0eq) was added. The reaction mixture was stirred under nitrogen at 90° C.until completion, as indicated by HPLC. The reaction mixture was cooledto rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate(10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesiumsulfate. Evaporation of solvent in vacuuo gave a crude oil. The crudealkylated aniline was purified by chromatography (Silica gel). Pureproduct was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) inanhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed byslow addition of valeryl chloride (5.0 eq), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to ambient temperature until completion, asindicated by HPLC. The solvent was removed in vacuuo, and the crudeamide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was by elution with 4-6%MeOH/DCM (yield 70 mg).

MS m/z 560 (M+H)⁺:

¹H NMR (CDCl₃): δ7.58 (d, 2H), 7.36 (d, 2H), 7.22 (d, 2H), 7.09 (d, 2H),7.04 (d, 2H), 6.93 (d, 2H), 4.03 (t, 2H), 2.56 (m, 10H), 1.94 (m, 2H),1.59 (m, 2H), 1.27 (m, 2H), 1.03 (t, 6H,), 0.97 (t, 3H), 0.82 (t, 3H)ppm.

Example 4732-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-imidazole

To a stirred solution of NaH (3 eq., 6.0 mmol) in DMF (10 mL) at rt,4′-hydroxyacetophenone (2.2 mmol) was added. The mesylate of1-(2-hydroxyethyl)-pyrrolidine (prepared from the corresponding alcoholand methanesulfonyl chloride) (2.0 mmol) was added to the reactionmixture and heated to 80° C. until completion according to GeneralProcedure Q1, as indicated by TLC or HPLC. After cooling to rt, thereaction mixture was diluted with cold water and the product wasisolated in EtOAc. The combined organic layers were washed withsaturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude alkylatedproduct was purified using silica gel column chromatography. Pureproduct was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol)in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.,1.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the residue was treated with saturatedsodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) andwashed with water (2×15 ml) and brine (15 ml). The organic layer wasdried over magnesium sulfate, and the solvent was removed in vacuuo toafford the desired product. The crude alpha-bromoacetophenone was usedfor further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) inanhydrous DMF (10 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slowaddition of the alpha-bromoacetophenone described above (1.0 mmol),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in EtOAc. The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of solvent in vacuuo affordedthe desired product. The crude alkylated aniline was used for furthertransformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followedby slow addition of valeryl chloride (2 eq., 2.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with water and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was purified using silica gel chromatography. Pure productwas obtained from 3-4% MeOH/DCM (Yield 40-45%).

To a stirred solution of the amide described above (0.5 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield: 105 mg).

MS m/z 51.6 (M)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.34 (d, 2H), 7.29 (d, 2H), 7.09(s, 1H), 7.05 (m, 4H), 6.95 (d, 2H), 4.19 (t, 2H), 3.05 (t, 2H), 2.84(m, 4H), 2.77 (t, 2H), 1.89 (m, 4H), 1.65 (m, 2H), 1.34 (m, 2H), 0.85(t, 3H) ppm

Example 4741-[2-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-piperidine

To a stirred solution of NaH (3 eq., 6.0 mmol) in DMF (10 mL) at rt,4′-hydroxyacetophenone (2.2 mmol) was added. The mesylate of1-(2-hydroxyethyl)-piperidine (prepared from the corresponding alcoholand methanesulfonyl chloride) (2.0 mmol) was added to the reactionmixture and heated to 80° C. until completion according to GeneralProcedure Q1, as indicated by TLC or HPLC. After cooling to rt, thereaction mixture was diluted with cold water and the product wasisolated in EtOAc. The combined organic layers were washed withsaturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude alkylatedproduct was purified using silica gel column chromatography. Pureproduct was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol)in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.,1.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the residue was treated with saturatedsodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) andwashed with water (2×15 ml) and brine (15 ml). The organic layer wasdried over magnesium sulfate, and the solvent was removed in vacuuo toafford the desired product. The crude alpha-bromoacetophenone was usedfor further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) inanhydrous DMF (10 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slowaddition of the alpha-bromoacetophenone described above (1.0 mmol),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in EtOAc. The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of solvent in vacuuo affordedthe desired product. The crude alkylated aniline was used for furthertransformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followedby slow addition of valeryl chloride (2 eq., 2.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with water and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was purified using silica gel chromatography. Pure productwas obtained from 3-4% MeOH/DCM (Yield 40-45%).

To a stirred solution of the amide described above (0.5 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield: 92 mg).

MS m/z 530 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.49 (d, 2H), 7.34 (d, 2H), 7.15 (d, 2H), 6.97(s, 1H), 6.93 (m, 4H), 6.84 (d, 2H), 4.18 (t, 2H), 3.33 (m, 4H), 2.81(t, 2H), 2.68 (t, 2H), 1.67 (m, 2H), 1.55 (m, 2H), 1.37 (m, 2H), 1.02(m, 4H) 0.65 (t, 3H) ppm

Example 475[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-2,2-dimethyl-propyl]-dimethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylateof 3-dimethylamino-2,2-dimethyl-1-propanol (prepared from thecorresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was addedto the reaction mixture and heated to 80° C. until completion accordingto General Procedure Q1, as indicated by TLC or HPLC. After cooling tort, the reaction mixture was diluted with water and the product wasisolated in EtOAc. The combined organic layers were washed withsaturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired product. The crude alkylatedproduct was purified using silica gel column chromatography. Pureproduct was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol)in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.,1.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the residue was treated with saturatedsodium bicarbonate and the product was isolated in EtOAc. The combinedorganic layers were washed with water (2×15 ml) and brine (15 ml). Theorganic layer was dried over magnesium sulfate, and the solvent wasremoved in vacuuo to afford the desired product. The crudealpha-bromoacetophenone was used for further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slowaddition of the alpha-bromoacetophenone described above (1.0 mmol),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in EtOAc. The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of solvent in vacuuo affordedthe desired product. The crude alkylated aniline was used for furthertransformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followedby slow addition of valeryl chloride (2 eq., 2.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with water and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was purified using silica gel chromatography. Pure productwas obtained from 3-4% MeOH/DCM (Yield 40-50%).

To a stirred solution of the amide described above (0.5 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM (yield: 105 mg).

MS m/z 532 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.34 (d, 2H), 7.29 (d, 2H), 7.09(s, 1H), 7.06 (d, 2H), 7.02 (d, 2H), 6.93 (d, 2H), 3.75 (s, 2H), 2.68(t, 2H), 2.42 (s, 2H), 2.35 (s, 6H), 1.65 (m, 2H), 1.29 (m, 2H), 1.05(s, 6H), 0.85 (t, 3H) ppm

Example 476[2-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-diisopropyl-amine

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylateof 2-(diisopropylamino)ethanol (prepared from the corresponding alcoholand methanesulfonyl chloride) (2.0 mmol) was added to the reactionmixture and heated to 80° C. until completion according to GeneralProcedure Q1, as indicated by TLC or HPLC. After cooling to rt, thereaction mixture was diluted with water and the product was isolated inEtOAc. The combined organic layers were washed with saturated sodiumbicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuuo to afford the desired product. The crude alkylated product waspurified using silica gel column chromatography. Pure product wasobtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol)in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.,1.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the residue was treated with saturatedsodium bicarbonate and the product was isolated in EtOAc. The combinedorganic layers were washed with water (2×15 ml) and brine (15 ml). Theorganic layer was dried over magnesium sulfate, and the solvent wasremoved in vacuuo to afford the desired product. The crudealpha-bromoacetophenone was used for further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slowaddition of the alpha-bromoacetophenone described above (1.0 mmol),according to General Procedure R2. The reaction mixture was stirredunder nitrogen at rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then diluted with cold water and the product wasisolated in EtOAc. The combined organic layers were washed with brineand dried over sodium sulfate. Evaporation of solvent in vacuuo affordedthe desired product. The crude alkylated aniline was used for furthertransformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followedby slow addition of valeryl chloride (2 eq., 2.0 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with water and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was purified using silica gel chromatography. Pure productwas obtained from 3-4% MeOH/DCM (Yield 40-50%).

To a stirred solution of the amide described above (0.5 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 4-6%MeOH/DCM.

MS m/z 546 (M+H)⁺:

Example 477[3-(4-{4-[4-(adamantan-1-ylmethoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

A stirred solution of the4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. After the addition, themesylate of 1-adamantylmethanol (1.1 eq) was added to the reactionmixture, and stirred at rt overnight, according to General Procedure T3.Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL).The organic layer was washed with H₂O (2×15 mL) and brine, and driedover sodium sulfate. The solvent was removed in vacuuo. Pure imidazolewas obtained from chromatography with 5-10% MeOH/DCM (yield 60 mg).

MS m/z 570 (M+H)⁺:

¹H NMR (CDCl₃): δ7.68 (d, 2H), 7.20 (d, 2H), 7.09 (s, 1H), 6.97 (d, 2H),6.90 (d, 2H), 4.06 (t, 2H), 3.5 (s, 2H), 2.6 (t, 2H), 2.58 (q, 4H), 2.52(d), 1.6-2.1 (m, 18H), 1.05 (t, 6H), 0.85 (d, 6H) ppm.

Example 478{3-[4-(4-{4-[3-(2,6-dichloro-phenyl)-4-methyl-isoxazol-5-ylmethyloxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-7% MeOH/DCM (yield -30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, -20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

To a stirred solution of the4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) obtained above in anhydrous DMF (5.0 mL) solid sodium hydride(60% dispersion in oil; 1.0 mmol) was added in portions. After theaddition, the requisite alkylhalide or the mesylate (prepared from thecorresponding alcohol and methanesulfonyl chloride) (1.1 eq) was addedto the reaction mixture. The reaction mixture was stirred at rtovernight. Et₂O (30 mL) was added to the reaction mixture followed byH₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine,and dried over sodium sulfate. The solvent was removed in vacuuo. Pureproduct was obtained from 5-10% MeOH/DCM (yield 57 mg).

MS m/z 661 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.65 (d, 2H), 7.2-7.44 (m, 5H), 7.08 (s, 1H), 6.96 (d,2H), 0.677 (d, 2H), 4.74 (s, 2H), 4.13 (t, 2H), 2.9-3.15 (m, 6H), 2.6(s, 3H), 2.51 (d, 2H), 2.3 (m, 3H), 1.35 (t, 6H), 0.83 (t, 6H) ppm

Example 479[3-(4-{4-[4-(4-bromo-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

A stirred solution of the4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of(4-bromophenyl)methanol (1.1 eq) was added to the reaction mixture, andstirred at rt overnight, according to General Procedure T3. Et₂O (30 mL)was added to the reaction mixture followed by H₂O (10 mL). The organiclayer was washed with H₂O (2×15 mL) and brine, and dried over sodiumsulfate. The solvent was removed in vacuuo. Pure imidazole was obtainedfrom chromatography with 5-10% MeOH/DCM (yield 95 mg).

MS m/z 591 (M+H)⁺:

¹H NMR (CDCl₃): δ7.7 (d, 2H), 7.5 (d, 2H), 7.32 (d, 2H), 7.21 (d, 2H),7.11 (s, 1H), 6.96 (m, 4H), 5.03 (s, 2H), 4.07 (t, 2H), 2.5-2.8 (m, 8H),2.0 (m, 3H), 1.07 (t, 6H), 0.84 (d, 6H) ppm.

Example 480[3-(4-{2-butyl-1-[4-(6-methoxy-naphthalen-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 6-methoxy-2-naphthol (10 mmol) to the reaction mixture andheating to 80° C. until the reaction was complete as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was poured into H₂O (100mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine(50 mL), and dried over sodium sulfate. The solvent was removed invacuuo to afford the desired4-(6-methoxy-naphthalen-2-yloxy)-1-nitrobenzene. The crude product wasused for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc(50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(6-methoxy-naphthalen-2-yloxy)aniline, which was used directly forfurther transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4.6 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 5.5 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of an 4-(6-methoxy-naphthalen-2-yloxy)aniline (5mmol) in anhydrous DMF (20 mL) DIEA (15 mmol) was added, followed byslow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(4.6 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation without additional purification.

To a stirred solution of alkylated4-(6-methoxy-naphthalen-2-yloxy)aniline described above (4.6 mmol) inanhydrous DCM (10 mL) at 0° C., TEA (3 eq., 15 mmol) was added, followedby slow addition of valeryl chloride (3 eq., 15 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the N-alkylated anilide (˜4.6 mmol) obtained asabove in acetic acid (10 mL), solid ammonium acetate (92 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×40 mL). The combined organic layers was washed with H₂O (2×40 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (yield500 mg).

MS m/z 578 (M+H)⁺:

¹H NMR (CDCl₃): δ8.51 (d, 1H), 8.42 (m, 1H), 8.31 (d, 1H), 7.75 (m, 2H),7.62 (m, 2H) 7.37 (s, 1H), 7.23 (m, 2H), 7.12 (m, 2H), 7.08 (s, 1H),6.97-6.79 (m, 2H), 3.98 (t, 2H), 3.41 (s, 3H), 3.23-3.05 (m, 6H), 2.75(m, 2H), 2.45 (m, 2H), 1.75-1.48 (m, 4H), 1.37 (t, 6H), 0.80 (m, 3H)ppm.

Example 481[3-(4-{2-butyl-1-[4-(naphthalen-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 2-naphthol (10 mmol) to the reaction mixture and heating to80° C. until the reaction was complete as indicated by TLC or HPLC.After cooling to rt, the reaction mixture was poured into H₂O (100 mL),extracated with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine (50mL), and dried over sodium sulfate. The solvent was removed in vacuuo toafford the desired 4-(naphthalen-2-yloxy)-1-nitrobenzene. The crudeproduct was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH(50 mL) and hydrogenated in the presence of 10% Pd/C (300 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(naphthalen-2-yloxy)aniline, which was used directly for furthertransformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4.6 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 5.5 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to it until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-(naphthalen-2-yloxy)aniline (1.2 eq., 5 mmol)in anhydrous DMF (5 mL) DIEA (3 eq. 15 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (4.6 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold H₂O and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was used for further transformation without additionalpurification.

To a stirred solution of alkylated 4-(naphthalen-2-yloxy)anilinedescribed above (4.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq.,15 mmol) was added, followed by slow addition of valeryl chloride (3eq., 15 mmol), according to General Procedure R3. The reaction mixturewas stirred under nitrogen at 0° C. for 1 h and allowed to warm to rtuntil completion, as indicated by TLC or HPLC. The solvent was removedin vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜4.6 mmol) obtained asabove in acetic acid (10 mL), solid ammonium acetate (92 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×50 mL). The combined organic layers was washed with H₂O (50 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (yield170 mg).

MS m/z 548 (M+H)⁺:

¹H NMR (CDCl₃): δ7.91 (t, 1H), 7.84 (t, 1H), 7.77 (m, 1H), 7.71 (m, 2H)7.56-7.42 (m, 4H), 7.32 (m, 2H), 7.18 (s, 1H), 7.16-7.03 (m, 2H),7.00-6.86 (m, 2H), 4.02 (t, 2H), 3.00-2.76 (m, 6H), 2.70 (m, 2H), 2.12(m, 2H), 1.44-1.28 (m, 4H), 1.23 (t, 6H), 0.93 (m, 3H) ppm.

Example 4822-butyl-4-[4-(4-ethyl-hexyloxy)-phenyl]-1-[4-(4-methoxy-naphthalen-1-yl-oxy)-phenyl]-1H-imidazole

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 4-methoxy-1-naphthol (10 mmol) to the reaction mixture andheating to 80° C. until the reaction was complete as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was poured into H₂O (100mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine(50 mL), and dried over sodium sulfate. The solvent was removed invacuuo to afford the desired4-(4-methoxynaphthalen-1-yloxy)-1-nitrobenzene. The crude product wasused for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc(50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(4-methoxy-naphthalen-1-yloxy)aniline, which was used directly forfurther transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2.3 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 2.7 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-(4-methoxy-naphthalen-1-yloxy)aniline (1.2eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added,followed by slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(2.3 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation.

To a stirred solution of alkylated4-(4-methoxynaphthalen-1-yloxy)aniline described above (2.3 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 7.5 mmol) was added, followedby slow addition of valeryl chloride (3 eq., 7.5 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The solvent was removed in vacuuo, and the crude amidewas used for further transformation.

To a stirred solution of the N-alkylated anilide (2.3 mmol) obtained asabove in acetic acid (5 mL), solid ammonium acetate (46 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (yield213 mg).

MS m/z 578 (M+H)⁺:

¹H NMR (CDCl₃): δ8.35 (dd, 1H), 7.60 (dd, 1H), 7.72 (m, 2H), 7.55 (m,2H), 7.24 (s, 1H), 7.23 (m, 2H), 7.15 (t, 1H), 7.04 (m, 2H), 6.90 (m,2H), 6.80 (d, 1H), 4.04 (s, 3H), 3.95 (t, 2H), 3.00-2.87 (m, 6H), 2.67(t, 2H), 2.10 (m, 2H), 1.65 (m, 2H), 1.38 (m, 2H), 1.21 (t, 6H), 0.95(m, 3H) ppm.

Example 483[3-(4-{2-butyl-1-[4-(dibenzofuran-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 2-hydroxydibenzofuran (10 mmol) to the reaction mixture andheating to 80° C. until the reaction was complete as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was poured into H₂O (100mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine(50 mL), and dried over sodium sulfate. The solvent was removed invacuuo to afford the desired 4-(dibenzofuran-2-yloxy)-1-nitrobenzene.The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc(50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(dibenzofuran-2-yloxy)aniline, which was used directly for furthertransformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2.3 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq, 2.7 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-(dibenzofuran-2-yloxy)aniline (1.2 eq., 2.5mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followedby slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(2.3 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation.

To a stirred solution of alkylated 4-(dibenzofuran-2-yloxy)anilinedescribed above (˜2.3 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3eq., 7.5 mmol) was added, followed by slow addition of valeryl chloride(3 eq., 7.5 mmol), according to General Procedure R3. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and allowed to warmto rt until completion, as indicated by TLC or HPLC. The solvent wasremoved in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the N-alkylated anilide (2.3 mmol) obtained asabove in acetic acid (5 mL), solid ammonium acetate (46 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (yield164 mg).

MS m/z 588 (M+H)⁺:

¹H NMR (CDCl₃): δ7.92 (d, 1H), 7.71 (m, 2H), 7.62 (d, 2H), 7.51 (t, 1H),7.37 (t, 1H), 7.32-7.26 (m, 3H), 7.23 (m, 2H), 7.16 (s, 1H), 7.13-7.09(m, 1H), 6.91 (d, 2H), 4.08 (t, 2H), 2.97-2.75 (m, 6H), 2.69 (t, 2H),2.19 (m, 2H), 1.69 (m, 2H), 1.39-1.25 (m, 2H), 1.29 (t, 6H), 0.89 (t,3H) ppm.

Example 4846-(4-{2-butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-naphthalen-2-ol

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 6-methoxy-2-naphthol (10 mmol) to the reaction mixture andheating to 80° C. until the reaction was complete as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was poured into H₂O (100mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine(50 mL), and dried over sodium sulfate. The solvent was removed invacuuo to afford the desired4-(6-methoxy-2-naphthalen-2-yloxy)-1-nitrobenzene. The crude product wasused for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc(50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(6-methoxy-naphthalen-2-yloxy)aniline, which was used directly forfurther transformation without additional purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(4.6 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 5.2 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of an 4-(6-methoxy-naphthalen-2-yloxy)aniline (5mmol) in anhydrous DMF (20 mL) DIEA (15 mmol) was added, followed byslow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(4.6 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation without additional purification.

To a stirred solution of alkylated 4-(6-methoxy-2-naphthalenoxy)anilinedescribed above (4.6 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3eq., 15 mmol) was added, followed by slow addition of valeryl chloride(3 eq., 15 mmol), according to General Procedure R3. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and allowed to warmto rt until completion, as indicated by TLC or HPLC. The solvent wasremoved in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the N-alkylated anilide (˜4.6 mmol) obtained asabove in acetic acid (10 mL), solid ammonium acetate (92 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×40 mL). The combined organic layers was washed with H₂O (2×40 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (Yield:19%).

The N-aryl imidazole (0.12 mmol) previously described was dissolved in 5mL of 48% aqueous HBr and heated to 90° C. for 36 h until the reactionwas complete by HPLC. The reaction mixture was cooled to rt and treatedwith ice-cold saturated aqueous sodium bicarbonate solution until pH 8.The mixture was extracted with EtOAc (2×15 mL). The combined organiclayers was washed with H₂O (2×15 mL) and brine, and dried over sodiumsulfate. Evaporation of the solvent in vacuuo afforded the demethylatedN-aryl imidazole. The crude product was purified using silica gel columnchromatography (2-5% MeOH/DCM) (yield 20 mg).

MS m/z 564 (M+H)⁺:

¹H NMR (CDCl₃): δ7.62 (d, 2H), 7.60 (s, 1H), 7.58-7.54 (m, 2H), 7.32 (d,1H), 7.18 (s, 1H), 7.16 (d, 1H), 7.15-7.10 (m, 2H), 7.08 (s, 1H), 7.02(d, 2H), 6.78 (d, 2H), 3.95 (t, 2H), 3.00-2.81 (m, 6H), 2.60 (t, 2H),2.12 (m, 2H), 1.56 (m, 2H), 1.30 (t, 2H), 1.21 (t, 6H), 0.75 (t, 3H)ppm.

Example 485[3-(4-{2-butyl-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

A mixture of 4-fluoroacetophone (50 mmol), 4-chlorophenol (75 mmol, 1.5eq), cesium carbonate (150 mmol, 3 eq) and anhydrous DMSO (80 mL) washeated with stirring at 90° C. for 20 h (monitored by TLC). Aftercooling to rt, the reaction mixture was treated with cold H₂O (150 mL),and the resulting mixture was extracted with ether (4×100 mL). Thecombined organic layers were washed with 2N NaOH (4×100 mL), H₂O (2×100mL) and brine (100 mL), and dried over anhydrous sodium sulfate. Thecrude 1-[4-(4-chlorophenoxy)phenyl]ethanone was purified by flashchromatography (eluting with 5-10% EtOAc in hexane) to give4-(4′-chlorophenoxy)acetophone as an almost colorless solid (yield:80%).

To a stirred solution of 4-fluoronitrobenzene (50 mmol) and3-diethylaminoproanol (70 mmol) dissolved in anhydrous THF (50 mL) at 0°C. and under a nitrogen stream was added KOBu^(t) (70 mmol) in portions,and the reaction mixture was allowed to warm to rt, and stirredovernight, according to General Procedure L1. The reaction mixture wasthen treated with cold H₂O (80 mL), and extracted with EtOAc (3×100 mL).The combined organic layers were washed with brine (2×60 mL) and driedover anhydrous sodium sulfate. Evaporation of the solvent in vacuuoafforded the desired N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine,which was used for further transformation without further purification(yield: ˜98%).

The crude N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (˜33 mmol) wasdissolved in MeOH (50 mL), and hydrogenated in the presence of 10% Pd/C(0.8 g) until the reaction was complete as indicated by LC-MS (˜4 h),according to General Procedure H. The reaction mixture was then filteredto remove the catalyst. The solvent was removed under high vacuum toafford N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine which was useddirectly for further transformation without further purification (yield:˜96%).

1-[4-(4-chlorophenoxy)phenyl]ethanone (24 mmol) was dissolved in1,4-dioxane (100 mL), and pyridine hydrotribromide (25.2 mmol, 1.05 eq)was added, according to General Procedure R1. After being stirred at rtfor 7 h (monitored by TLC), the reaction was quenched with cold H₂O (100mL). The resulting mixture was extracted with ether (4×100 mL). Thecombined ether extracts were washed with brine (3×50 mL), and dried overanhydrous sodium sulfate. The solvent was then removed in vacuuo and thecrude 2-bromo-1-[4-(4-chlorophenoxy)phenyl]ethanone was directly usedfor further transformation.

To a stirred solution of ice-coldN,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (22 mmol, 1.1 eq)dissolved in DCM (40 mL) was added dropwise a solution of the2-bromo-1-[4-(4-chlorophenoxy)phenyl]ethanone (20 mmol) dissolved in DMF(30 mL), according to General Procedure R2. The mixture was stirred at0° C. for 3 h, and then allowed to warm to rt, continuing the stirringfor additional 2 h (monitored by LC-MS). The reaction mixture wastreated with saturated sodium bicarbonate (100 mL), and the resultingmixture was extracted with EtOAc (4×100 mL). The combined EtOAc extractswere washed with brine (3×50 mL), and dried over anhydrous sodiumsulfate. The solvent was removed in vacuuo, and the crude product waspurified by silica gel column chromatography eluting with 10% MeOH inEtOAc+0.2% TEA (overall yield from1-[4-(4-chlorophenoxy)phenyl]ethanone: 60%).

To a stirred solution of the alkylated aniline described above (10 mmol)dissolved in anhydrous DCM (100 mL) at 0° C., TEA (40 mmol, 4 eq) wasadded, followed by a slow addition of valeryl chloride (20 mmol, 2 eq),according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 2 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

The crude amide described above (˜6 mmol) was suspended in acetic acid(10 mL), and ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C. for 6 h(as monitored by LC-MS). The reaction mixture was then cooled down andneutralized with saturated sodium bicarbonate and solid sodiumcarbonate. The resulting mixture was extracted with EtOAc (4×100 mL).The combined EtOAc extracts were washed with H₂O (2×60 mL) and brine(2×60 and dried over anhydrous sodium sulfate. The solvent was removedin vacuuo, and the crude product was purified by silica gel columnchromatography eluting with 10% MeOH in EtOAc+0.2% TEA affording Example485.

MS m/z 532 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.83 (t, 3H), 1.04 (t, 6H), 1.28 (m, 2H), 1.63(m, 2H), 1.96 (m, 2H), 2.56 (q, 4H), 2.61-2.65 (m, 4H), 4.06 (t, 2H),6.93 (d, 2H), 6.98 (d, 2H), 7.00 (d, 2H), 7.16 (s, 1H), 7.22 (d, 2H),7.26 (d, 2H), 7.76 (d, 2H) ppm.

Example 486[3-(4-{2-(4-tert-butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(80 mmol) in MeOH (200 mL) at rt, pyrrolidone hydrotribromide (96 mmol,1.2 eq) was added in portions at rt, according to General Procedure R1.The reaction mixture was stirred at rt for 2 h (monitored by LC-MS). Thesolvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

The solution of the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone dissolved inanhydrous DMF (180 mL) was chilled to 0° C., and4-(4′-chlorophenoxy)aniline (88 mmol, 1.1 eq) was added, followed byslowly adding DIEA (240 mmol, 3 eq), according to General Procedure R2.After being stirred at 0° C. for 1 h and at rt for additional 4 h, thereaction mixture was treated with saturated sodium bicarbonate (250 mL).The resulting mixture was extracted with EtOAc (4×200 mL). The combinedEtOAc extracts were washed with brine (3×100 mL), and dried overanhydrous sodium sulfate. The solvent was removed in vacuuo, and thecrude product was purified by silica gel column chromatography elutingwith 10% MeOH in EtOAc+0.2% TEA.

Oxayl chloride (420 mmol, 3 eq) was added slowly to an ice-cold solutionof 4-t-butylcyclohexanecarboxylic acid (140 mmol) dissolved in anhydrousDCM (80 mL), and the reaction mixture was stirred at 0° C. for 3 h andat rt for additional 3 h. The solvent was removed in vacuuo, and theresulting acid chloride was pumped under high vacuum for about 30 min,and used for next step reaction without further purification.

To a stirred solution of the2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanonedescribed above (35 mmol) dissolved in anhydrous DCM (200 mL) at 0° C.,TEA (140 mmol, 4 eq) was added, followed by a slow addition of thefreshly prepared acid chloride (70 mmol, 2 eq). The reaction mixture wasstirred under nitrogen at 0° C. for 2 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

The crude amide described above (˜35 mmol) was suspended in acetic acid(50 mL), and ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for 6h (as monitored by LC-MS). The reaction mixture was then cooled down andneutralized with saturated sodium bicarbonate and solid sodiumcarbonate. The resulting mixture was extracted with EtOAc (4×200 mL).The combined EtOAc extracts were washed with H₂O (2×100 mL) and brine(2×100 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude product was purified by silica gelcolumn chromatography eluting with 10% MeOH in EtOAc+0.2% TEA affordingthe title compound as cis/trans (1:2 ratio) mixture (yield 14.5 g).

LC: 1.06 min; MS: m/z 614 (M+H)⁺

Example 487[3-{-4-[1-[4-(4-chloro-phenoxy)-phenyl]-2-(4-ethyl-cyclohexyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(80 mmol) in MeOH (200 mL) at rt, pyrrolidone hydrotribromide (96 mmol,1.2 eq) was added in portions at rt, according to General Procedure R1.The reaction mixture was stirred at rt for 2 h (monitored by LC-MS). Thesolvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly usedfor further transformation.

The solution of the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone dissolved inanhydrous DMF (180 mL) was chilled to 0° C., and4-(4′-chlorophenoxy)aniline (88 mmol, 1.1 eq) was added, followed byslowly adding DIEA (240 mmol, 3 eq), according to General Procedure R2.After being stirred at 0° C. for 1 h and at it for additional 4 h, thereaction mixture was treated with saturated sodium bicarbonate (250 mL).The resulting mixture was extracted with EtOAc (4×200 mL). The combinedEtOAc extracts were washed with brine (3×100 mL), and dried overanhydrous sodium sulfate. The solvent was removed in vacuuo, and thecrude product was purified by silica gel column chromatography elutingwith 10% MeOH in EtOAc+0.2% TEA (yield: 45%).

Oxayl chloride (3 mmol, 3 eq) was added slowly to an ice-cold solutionof trans-4-ethylcyclohexanecarboxylic acid (1 mmol) dissolved inanhydrous DCM (5 mL), and the reaction mixture was stirred at 0° C. for2 h and at it for additional 1 h. The solvent was removed in vacuuo, andthe resulting acid chloride was pumped under high vacuum for about 30min, and used without further purification.

To a stirred solution of the2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone(0.3 mmol) described above dissolved in anhydrous DCM (10 mL) at 0° C.,TEA (1.2 mmol, 4 eq) was added, followed by slow addition of the freshlyprepared acid chloride (˜1 mmol, ˜3 eq). The reaction mixture wasstirred under nitrogen at 0° C. for 2 h and allowed to warm to rt untilcompletion, as indicated by LC-MS. The solvent was removed in vacuuo,and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.3 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜30 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C. for 3h (as monitored by LC-MS). The reaction mixture was then cooled to rtand neutralized with saturated sodium bicarbonate. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts werewashed with brine (3×20 ml), and dried over anhydrous sodium sulfate.The solvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH/EtOAc+0.2% Et₃N(yield 123 mg).

MS m/z 586 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.85 (t, 3H), 1.06 (t, 6H), 1.16-1.82 (m,12H), 1.96 (m, 2H), 2.61 (q, 4H), 2.68 (t, 21-1), 4.01 (t, 2H), 6.89 (d,2H), 7.03 (d, 2H), 7.06 (d, 2H), 7.08 (s, 1H), 7.27 (d, 2H), 7.35 (d,2H), 7.68 (d, 2H) ppm.

Example 488[4-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-phenyl]-(1-ethyl-piperidin-4-ylmethyl)-amine

To a stirred solution of the 4′-(4-nitro-phenoxy)acetophenone (2 mmol)in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.,2.2 mmol) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the residue was treated with saturatedsodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) andwashed with water (2×15 ml) and brine (15 ml). The organic layer wasdried over magnesium sulfate, and the solvent was removed in vacuuo toafford the desired product. The crude alpha-bromoacetophenone was usedfor further transformation.

To a stirred solution of the 4-chloro-phenoxy aniline (1.2 eq., 2.2mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 6 mmol) was added, followedby slow addition of the alpha-bromoacetophenone described above (1.6mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation.

To a stirred solution of alkylated aniline described above (1.6 mmol) inanhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followedby slow addition of valeryl chloride (2 eq., 3.2 mmol), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to rt until completion, as indicatedby TLC or HPLC. The reaction mixture was then diluted with water and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 90° C.overnight. The reaction mixture was then cooled to rt and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 30-40%ethylacetate/hexane (yield 50-55%).

The cyclized imidazole intermediate obtained above (0.5 mmol) obtainedabove was dissolved in MeOH (5 mL) and hydrogenated in the presence of10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, accordingto General Procedure H. The reaction mixture was then filtered to removethe catalyst. The solvent was removed in vacuuo to afford the desiredreduced imidazole, which was used directly for further transformationwithout further purification.

To a stirred solution of N-Boc-4-piperidineacetic acid (1.2 eq., 0.6mmol) in anhydrous DCM (2 mL) was added DCC-PS (1.5 eq., 0.75 mmol). Thesolution was allowed to shake at rt for 20-30 min. This was followed byaddition of the reduced cyclized imidazole described above (0.5 mmol).The reaction mixture was shaken overnight at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then filtered and theproduct was isolated in DCM. The solvent was removed in vacuuo, and thecrude amide was used for further transformation.

To a stirred solution of the amide described above (0.5 mmol) inanhydrous THF (2 mL) at 0° C., borane/THF (3 eq, 1.5 mmol) was added.The reaction mixture was stirred under nitrogen at 0° C. for 1 h andallowed to warm to rt until completion, as indicated by TLC or HPLC. Thereaction mixture was then cooled to rt and the solvent was removed invacuuo to give the product imidazole, which was purified by columnchromatography (Silica gel). Pure product was obtained from 3-4%MeOH/DCM (yield 150 mg).

MS m/z 635 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 8.01 (s, 1H), 7.84 (d, 2H), 7.65 (d, 2H),7.59 (d, 2H), 7.44 (d, 2H), 7.22 (m, 6H), 7.12 (d, 2H), 3.65 (d, 2H),3.45 (d, 2H), 3.03 (t, 2H), 3.18 (m, 2H), 2.98 (m, 4H), 2.15 (m, 2H),1.71 (m, 3H), 1.39 (m, 5H), 0.85 (t, 3H) ppm

Example 489[4-{1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-(3-diethylaminopropoxy)-phenyl]-1H-imidazol-2-yl}-butyricacid methyl ester

As described in Example 406,2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone(0.5 mmol) was dissolved in anhydrous DCM (10 mL) and cooled to 0° C.TEA (2 mmol, 4 eq) was added to the reaction mixture, followed by slowaddition of methyl 4-(chloroformyl)butyrate (1.5 mmol, 3 eq), accordingto General Procedure R3. The reaction mixture was stirred under nitrogenat 0° C. for 2 h and allowed to warm to rt until completion, asindicated by LC-MS. The solvent was removed in vacuuo, and the crudeamide was used directly for further transformation.

To a stirred solution of the amide described above in acetic acid (2mL), ammonium acetate (excess, ˜30 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 100° C. for 3 h (asmonitored by LC-MS). The reaction mixture was then cooled down andneutralized with saturated sodium bicarbonate. The resulting mixture wasextracted with EtOAc (3×50 mL). The combined EtOAc extracts were washedwith brine (3×20 mL), and dried over anhydrous sodium sulfate. Thesolvent was removed in vacuuo, and the pure product was obtained bysilica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA(yield: ˜70%) (yield 202 mg).

MS m/z 576 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.04 (t, 6H), 1.94 (m, 2H), 2.02 (m, 2H), 2.39(t, 2H), 2.56 (q, 4H), 2.63 (t, 2H), 2.72 (t, 2H), 3.59 (s, 3H), 4.02(t, 2H), 6.91 (d, 2H), 7.03 (d, 2H), 7.07 (d, 2H), 7.14 (s, 1H), 7.29(d, 2H), 7.35 (d, 2H), 7.68 (d, 2H) ppm.

Example 490[3-(4-{2-butyl-1-[4-(4-chloro-2-cyclohexyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (10mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 4-chloro-2-cyclohexylphenol (10 mmol) to the reactionmixture and heating to 80° C. until the reaction was complete asindicated by TLC or HPLC. After cooling to rt, the reaction mixture waspoured into EtOAc (80 ml), washed with H₂O (2×40 ml) and brine (60 mL),and dried over sodium sulfate. The solvent was removed in vacuuo toafford the desired 4-(4-chloro-2-cyclohexylphenoxy)-1-nitrobenzene. Thecrude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in MeOH(20 mL), and treated with SnCl₂.2H₂O (50 mmol), according to GeneralProcedure I. The reaction mixture was heated under reflux untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. Theresidue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueousNaOH, brine and dried over sodium sulfate. The solvent was removed invacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy) aniline,which was used directly for further transformation without furtherpurification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq, 2.9 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-(4-chloro-2-cyclohexylphenoxy) aniline (1.2eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added,followed by slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(2.4 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield ˜50-60%).

To a stirred solution of alkylated 4-(4-chloro-2-cyclohexylphenoxy)aniline described above (2.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA(3 eq., 7.5 mmol) was added, followed by slow addition of valerylchloride (3 eq., 7.5 mmol), according to General Procedure R3. Thereaction mixture was stirred under nitrogen at 0° C. for 1 h and allowedto warm to rt until completion, as indicated by TLC or HPLC. The solventwas removed in vacuuo, and the crude amide was used for furthertransformation.

To a stirred solution of the N-alkylated anilide (˜2.4 mmol) obtained asabove in acetic acid (5 mL), solid ammonium acetate (46 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (yield118 mg).

MS m/z 614 (M+H)⁺:

¹H NMR (CDCl₃) δ7.86 (d, 1H), 7.63 (d, 2H), 7.25 (d, 2H), 7.18 (s, 1H),7.08 (s, 1H), 6.94 (d, 2H), 6.81 (d, 2H), 6.80 (d, 1H, 6.8 Hz), 4.12 (m,2H), 3.20 (m, 2H), 2.98-2.79 (m, 6H), 2.60 (t, 2H), 2.21-2.19 (m, 2H),2.15-2.05 (m, 1H), 1.78-1.72 (m, 2H), 1.59-1.50 (m, 2H), 1.36-1.24 (m,4H), 1.21 (t, 6H), 0.84 (m, 4H), 0.79 (m, 3H) ppm.

Example 491[3-(4-{1-[4-(biphenyl-4-yloxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at room temperature, solid K₂CO₃ (30 mmol) was added followed byaddition of 4-hydroxybiphenyl (10 mmol) to the reaction mixture andheating to 80° C. until the reaction was complete as indicated by TLC orHPLC. After cooling to room temperature to room temperature, thereaction mixture was poured into EtOAc (100 mL), washed with water (2×50mL) and brine (50 mL), and dried over sodium sulfate. The solvent wasremoved in vacuo to afford the desired4-(biphenyl-4-oxy)-1-nitrobenzene. The crude product was used forfurther transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc(40 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) untilcompletion, as indicated by TLC or HPLC. The reaction mixture was thenfiltered to remove the catalyst. The solvent was removed in vacuo toafford the desired 4-(biphenyl-4-oxy)aniline, which was used directlyfor further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at room temperature, solid K₂CO₃ (153 mmol) was added. The mesylate of3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) wasadded to the reaction mixture and heated to 80° C. until completion, asindicated by TLC or HPLC. After cooling to room temperature, thereaction mixture was quenched by treating the mixture with saturatedsodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) andwashed with water (2×50 mL) and brine (50 mL). The organic layer wasdried over sodium sulfate, and the solvent was removed in vacuuo toafford the desired product. The crude alkylated product was used forfurther transformation after purifying using silica gel columnchromatography (1-4% methanol/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 2.9 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-(biphenyl-4-oxy)aniline (1.2 eq., 2.5 mmol)in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slowaddition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (2.4 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold H₂O and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure productobtained from 2-4% MeOH/DCM (yield ˜13%).

To a stirred solution of alkylated 4-(biphenyl-4-oxy)aniline describedabove (0.3 mmol) in anhydrous DCM (3 mL) at 0° C., TEA (3 eq., 0.9 mmol)was added, followed by slow addition of valeryl chloride (3 eq., 0.9mmol), according to General Procedure R3. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜0.3 mmol) obtained asabove in acetic acid (3 mL), solid ammonium acetate (6 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM).

MS m/z 574 (M+H)⁺

¹H NMR (CDCl₃) δ7.86 (d, 1H), 7.63 (d, 2H), 7.25 (d, 2H), 7.18 (s, 1H),7.08 (s, 1H), 6.94 (d, 2H), 6.81 (d, 2H), 6.80 (d, 1H), 4.12 (m, 2H),3.20 (m, 2H), 2.98-2.79 (m, 6H), 2.60 (t, 2H), 2.21-2.19 (m, 2H),2.15-2.05 (m, 1H), 1.78-1.72 (m, 2H), 1.59-1.50 (m, 2H), 1.36-1.24 (m,4H), 1.21 (t, 6H), 0.84 (m, 4H), 0.79 (m, 3H) ppm

Example 492[3-(4-{1-[4-(4-bromo-phenoxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 4-bromophenol (10 mmol) to the reaction mixture and heatingto 80° C. until the reaction was complete as indicated by TLC or HPLC.After cooling to rt, the reaction mixture was poured into EtOAc (100mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodiumsulfate. The solvent was removed in vacuuo to afford the desired4-bromophenoxy-1-nitrobenzene. The crude product was used for furthertransformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc(50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-bromophenoxyaniline, which was used directly for furthertransformation without additional purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 2.9 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-bromophenoxyaniline (1.2 eq., 2.5 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slowaddition of the 2-bromo-1-{(4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (2.4 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold H₂O and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure productobtained from 2-4% MeOH/DCM.

To a stirred solution of alkylated 4-bromophenoxyaniline described above(0.45 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 1.35 mmol) wasadded, followed by slow addition of valeryl chloride (3 eq., 1.35 mmol),according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜0.45 mmol) obtainedas above in acetic acid (3 mL), solid ammonium acetate (9 mmol) wasadded in one portion, according to General Procedure R4. The reactionmixture was then heated to 100° C. overnight. The reaction mixture wascooled to rt, and treated with saturated aqueous sodium bicarbonatesolution while stirring to until the pH was 7-8. The contents wereextracted with EtOAc (2×15 mL). The combined organic layers was washedwith H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporationof the solvent in vacuuo afforded the desired N-aryl imidazole. Thecrude product was purified using silica gel column chromatography (2-5%MeOH/DCM) (yield 66 mg).

MS m/z 577 (M+H)⁺:

¹H NMR (CDCl₃): δ7.63 (d, 2H), 7.43 (d, 2H), 7.23 (d, 2H), 7.08 (s, 1H),7.02 (d, 2H), 6.90 (d, 2H), 6.83 (d, 2H) 4.05 (t, 2H), 2.92-2.72 (m,6H), 2.60 (t, 2H), 2.05-2.15 (m, 2H), 1.60 (m, 2H), 1.33 (m, 2H), 1.20(t, 6H), 0.80 (t, 3H) ppm

Example 493N-[4-(4-{2-butyl-4-[4-(3-diethylamino-porpoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]-acetamide

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for 1 h andat rt for 1 h (until the reaction was complete by HPLC). The solvent wasremoved and to this saturated aqueous sodium bicarbonate was added. Theproduct was extracted with EtOAc (3×) and washed with sodium bicarbonateand water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and theproduct 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified byflash chromatography (going by increasing gradient up to 10% MeOH inDCM). The overall yield was 60%.

4-Acetamidophenol (10 mmol) was dissolved in 15 ml of anhydrous DMF andpotassium carbonate (30 mmol) was added with stirring at rt.4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was thenheated under reflux at 80° C. for 18 h. The reaction was quenched with30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc(3×50 ml) and washed with sodium bicarbonate and water. EtOAc layer wasdried over anhydrous sodium sulfate and filtered, after which thesolvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH(30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-(3,4-dichlorophenoxy)aniline, which was used directly for furthertransformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-(4-acetamidophenoxy) aniline (1 eq, 2 mmol) inanhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by additionof the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone describedabove (2 mmol), according to General Procedure R2. The reaction mixturewas stirred under nitrogen at rt until completion, as indicated by TLCor HPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield 54%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 210mg).

MS m/z 555 (M+H)⁺:

¹H NMR: (CDCl₃): δ7.68 (d, 2H), 7.51 (d, 2H), 7.25 (d, 2H), 7.13 (s,1H), 6.88-7.00 (m, 6H), 4.02 (t, 2H), 2.62-2.70 (m, 8H), 2.20 (s, 3H),2.16 (m, 2H), 1.97 (m, 2H), 1.16 (m, 2H), 1.05 (t, 6H), 0.83 (t, 3H) ppm

Example 494(3-{4-[2-butyl-1-(4-p-tolyloxy-phenyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA(40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To thismixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowlywith stirring and the reaction mixture was stirred at 0° C. for an hourand at rt for another hour (until the reaction was complete by HPLC).The solvent was removed and to this saturated aqueous sodium bicarbonatewas added. The product was extracted with EtOAc (3×) and washed withsodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved inanhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) andpotassium carbonate (60 mmol, 3 eq) were added. The mixture was heatedunder reflux at 85° C. for 18 h (until the reaction was complete byHPLC), after which it was cooled to rt. Saturated aqueous sodiumbicarbonate was added to the mixture, which was then transferred to aseparatory funnel. The product was extracted with EtOAc and washed withsodium bicarbonate and water. The solvent was removed in vacuuo and theproduct 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified byflash chromatography (going by increasing gradient up to 10% MeOH inDCM). The overall yield was 60%.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-tolyloxy aniline (1 eq, 2 mmol) in anhydrous DMF (6mL), DIEA (3 eq 6 mmol) was added, followed by addition of the2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described above(2 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield 56%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 204mg).

MS m/z 512 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.68 (d, 2H), 7.23 (d, 2H), 7.19 (d, 2H), 7.13 (s,1H), 7.04 (d, 2H), 6.97 (d, 2H), 6.87 (d, 2H) 4.04 (t, 2H), 2.88-2.96(m, 8H), 2.36 (s, 3H), 2.12 (m, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.18(t, 6H), 0.83 (t, 3H) ppm

Example 495[3-(4-{2-butyl-1-[4-(4-fluoro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 4-fluorophenol (10 mmol) to the reaction mixture and heatingto 80° C. until the reaction was complete as indicated by TLC or HPLC.After cooling to rt, the reaction mixture was poured into EtOAc (100mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodiumsulfate. The solvent was removed in vacuuo to afford the desired4-fluorophenoxy-1-nitrobenzene. The crude product may be used forfurther transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc(30 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) untilcompletion according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford the desired4-fluorophenoxyaniline, which was used directly for furthertransformation without additional purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt; the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2.3 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 2.8 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-fluorophenoxyaniline (1.2 eq., 2.5 mmol) inanhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slowaddition of the 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanonedescribed above (2.3 mmol), according to General Procedure R2. Thereaction mixture was stirred under nitrogen at rt until completion, asindicated by TLC or HPLC. The reaction mixture was then diluted withcold H₂O and the product was isolated in EtOAc. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure productobtained from 2-4% MeOH/DCM (yield ˜30%).

To a stirred solution of alkylated 4-fluorophenoxyaniline describedabove (0.8 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 2.4 mmol)was added, followed by slow addition of valeryl chloride (3 eq., 2.4mmol), according to General Procedure R3. The reaction mixture wasstirred under nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜0.8 mmol) obtained asabove in acetic acid (3 mL), solid ammonium acetate (16 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (yield214 mg).

MS m/z 516 (M+H)⁺:

¹H NMR (CDCl₃): δ7.88 (d, 2H), 7.46 (d, 2H), 7.23 (d, 2H), 7.31 (s, 1H),7.22 (d, 2H), 7.09 (d, 2H), 7.06 (d, 2H) 4.22 (t, 2H), 3.16 (m, 2H),3.21 (q, 4H), 2.84 (t, 2H), 2.39-2.19 (m, 2H), 1.83 (m, 2H), 1.50 (m,2H), 1.35 (t, 6H), 1.03 (t, 3H) ppm

Example 496[3-(4-{2-butyl-1-[4-(4-chloro-3-ethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20mL) at rt, solid potassium carbonate (30 mmol) was added followed byaddition of 4-chloro-3-ethylphenol (10 mmol) to the reaction mixture andheating to 80° C. until the reaction was complete as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was poured into EtOAc(100 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried oversodium sulfate. The solvent was removed in vacuuo to afford the desired4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene. The crude product was usedfor further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in MeOH(20 mL), and treated with SnCl₂2H₂O (50 mmol), according to GeneralProcedure I. The reaction mixture was heated under reflux untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. Theresidue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueousNaOH (50 mL), brine and dried over sodium sulfate. The solvent wasremoved in vacuuo to afford the desired 4-chloro-3-ethylphenoxyaniline,which was used directly for further transformation without additionalpurification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL)at rt, solid potassium carbonate (153 mmol) was added. The mesylateprepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76mmol) was added to the reaction mixture and heated to 80° C. untilcompletion according to General Procedure Q1, as indicated by TLC orHPLC. After cooling to rt, the reaction mixture was quenched by treatingthe mixture with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50mL). The organic layer was dried over sodium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylatedproduct was used for further transformation after purifying using silicagel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone(2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidonehydrotribromide (1.2 eq., 2.9 mmol) was added, according to GeneralProcedure R1. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and was allowed to warm to rt until completion, as indicated byTLC or HPLC. The solvent was then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a stirred solution of 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (1.2eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added,followed by slow addition of the2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above(2.4 mmol), according to General Procedure R2. The reaction mixture wasstirred under nitrogen at rt until completion, as indicated by TLC orHPLC. The reaction mixture was then diluted with cold H₂O and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline wasused for further transformation.

To a stirred solution of alkylated4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene described above (˜2.4 mmol)in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 7.5 mmol) was added,followed by slow addition of valeryl chloride (3 eq., 7.5 mmol),according to General Procedure R3. The reaction mixture was stirredunder nitrogen at 0° C. for 1 h and allowed to warm to rt untilcompletion, as indicated by TLC or HPLC. The solvent was removed invacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜2.4 mmol) obtained asabove in acetic acid (3 mL), solid ammonium acetate (46 mmol) was addedin one portion, according to General Procedure R4. The reaction mixturewas then heated to 100° C. overnight. The reaction mixture was cooled tort, and treated with saturated aqueous sodium bicarbonate solution whilestirring to until the pH was 7-8. The contents were extracted with EtOAc(2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) andbrine, and dried over sodium sulfate. Evaporation of the solvent invacuuo afforded the desired N-aryl imidazole. The crude product waspurified using silica gel column chromatography (2-5% MeOH/DCM) (yield60 mg).

MS m/z 560 (M+H)⁺:

¹H NMR (CDCl₃): δ8.30 (d, 1H), 7.64 (d, 2H), 7.28 (d, 2H), 7.21 (s, 1H),7.18 (s, 1H), 7.03 (d, 2H), 6.90 (m, 1H), 6.83 (d, 2H) 4.22 (t, 2H),2.85-2.75 (m, 2H), 2.89 (q, 4H), 2.61 (m, 2H), 2.24 (t, 2H), 2.14 (d,3H), 2.09-1.98 (m, 2H), 1.58 (m, 2H), 1.28 (m, 2H), 1.25 (t, 6H), 0.93(t, 3H) ppm.

Example 497{2-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}-ethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (4 mmol) in DMF (10 mL)at rt, solid potassium carbonate (12.0 mmol) was added.4-chlorophenthoxy mesylate (prepwered from the 4-chlorophemethanol andmethanesulfonyl chloride) (4.4 mmol) was added to the reaction mixtureand heated to 80° C. until completion according to General Procedure Q1,as indicated by TLC or HPLC. After cooling to rt, the reaction mixturewas quenched with saturated sodium bicarbonate. The aqueous layer waspoured into EtOAc (30 ml) and washed with water (2×15 ml) and brine (15ml). The organic layer was dried over magnesium sulfate, and the solventwas removed in vacuuo to afford the desired1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylatedproduct was purified by silica gel chromatography and the pure productobtained from 10% EtOAc/hexanes (yield 70%).

To a stirred solution of 4-fluoronitrobenzene (4.0 mmol) in anhydrousTHF (12 mL) at 0° C., a 1M solution of a potassium alkoxide (4.4 mmol)in THF (may be generated by adding the N-Boc,N-ethyl ethanolamine to a1M solution of KOBu^(t) in THF) was added dropwise and under a nitrogenstream, according to General Procedure L1. The reaction mixture wasstirred at 0° C. until completion, as indicated by TLC or HPLC. Thesolvent was removed and the reaction mixture was then treated with coldH₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. Thecrude product could be used directly for further transformation.

The nitro intermediate (2 mmol) obtained above was dissolved in EtOH (8mL) and hydrogenated in the presence of 10% Pd/C (10 mg) untilcompletion, according to General Procedure H, as indicated by TLC orHPLC. The reaction mixture was then filtered to remove the catalyst. Thesolvent was removed in vacuuo to afford4-(N-Boc-N-ethylaminoethoxy)aniline, which was used directly for furthertransformation without further purification (yield 80%).

To a stirred solution of 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone(2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide(1.2 eq) was added, according to General Procedure R1. The reactionmixture was stirred under nitrogen at 0° C. for 1 h and was allowed towarm to rt until completion, as indicated by TLC or HPLC. The solventwas then removed in vacuuo and the crude2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used forfurther transformation.

To a solution of 4-(N-Boc-N-ethylethoxy)aniline (1 eq, 2 mmol) inanhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by additionof the 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone describedabove (2 mmol), according to General Procedure R2. The reaction mixturewas stirred under nitrogen at rt until completion, as indicated by TLCor HPLC. The reaction mixture was then diluted with cold water and theproduct was isolated in EtOAc. The combined organic layers were washedwith brine and dried over sodium sulfate. Evaporation of solvent invacuuo afforded the desired product. The crude alkylated aniline waspurified by chromatography (Silica gel). Pure product obtained from 2-4%MeOH/DCM (yield 52%).

To a stirred solution of alkylated aniline described above (1 mmol) inanhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed bya slow addition of valeryl chloride (3 eq, 3 mmol), according to GeneralProcedure R3. The reaction mixture was stirred under nitrogen at 0° C.for 1 h and allowed to warm to rt until completion, as indicated by TLCor HPLC. The solvent was removed in vacuuo, and the crude amide was usedfor further transformation.

To a stirred solution of the amide described above (1 mmol) in aceticacid (4 mL), ammonium acetate (20 eq) was added, according to GeneralProcedure R4. The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was then cooled to rt and neutralized with saturatedsodium bicarbonate solution. Usual extractive work up with EtOAc gavethe product imidazole, which was purified by column chromatography(Silica gel). Pure product obtained from 4-6% MeOH/DCM was treated withHCl in dioxane for 2 h to give the hydrochloride salt of{2-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}-ethyl-amine(yield 177 mg).

MS m/z 518 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.2 (m, 4H), 7.1 (m, 3H),6.8-7.0 (m, 4H), 4.0-4.3 (m, 6H), 3.0-3.2 (m, 6H), 2.9 (m, 2H), 2.6 (m,2H), 1.2 (t, 3H), 0.8 (t, 3H) ppm

Example 498[3-(4-{5-butyl-4-[4-(3,3-diphenyl-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-2,2-dimethyl-propyl]-dimethyl-amine

To a stirred solution of ice-cold 4-hydroxy-n-hexanophenone (18 mmol),3,3-diphenyl-1-propanol (22.6 mmol, 1.25 eq), triphenylphosphine (22.6mmol, 1.25 eq) dissolved in anhydrous THF (100 mL) was added dropwisediisopropyl azodicarboxylate (DIAD) (22.6 mmol, 1.25 eq). The reactionmixture was stirred at 0° C. for 1 h, and then allowed to warm to rt,continuing the stirring for additional 6 h (monitored by TLC). Thesolvent was removed in vacuuo, and the crude product was purified bysilica gel column chromatography eluting with 10% EtOAc in hexane(yield: 100%).

The acetophone described as above (18 mmol) was dissolved in 1,4-dioxane(100 mL), and treated with pyridine hydrotribromide (18.9 mmol, 1.05eq), according to General Procedure R1. After stirring at rt for 6 h(monitored by TLC), the reaction was quenched with cold H₂O (100 mL).The resulting mixture was extracted with EtOAc (4×100 mL). The combinedEtOAc extracts were washed with brine (3×50 mL), and dried overanhydrous sodium sulfate. The solvent was then removed in vacuuo and thecrude alpha-bromoacetophenone was directly used for furthertransformation.

To a stirred solution of the crude alpha-bromoacetophenone described asabove (˜12 mmol) and 4-benzyloxyaniline (12 mmol) dissolved in DMF (40mL), DIEA (36 mmol, 3 eq) was added at rt, and the mixture was stirredat the same temperature for 12 h, according to General Procedure R2(monitored by TLC and LC-MS). The reaction mixture was treated withsaturated sodium bicarbonate (100 mL), and the resulting mixture wasextracted with EtOAc (4×100 mL). The combined EtOAc extracts were washedwith brine (3×50 mL), and dried over anhydrous sodium sulfate. Thesolvent was removed in vacuuo, and the crude product was purified bysilica gel column chromatography eluting with 10-15% EtOAc in hexane(overall yield from the acetophone: ˜50%).

To a stirred solution of ice-cold the alkylated aniline (1.7 mmol)obtained above and DMAP (3.4 mmol, 2 eq) dissolved in anhydrous DCM (200mL), isovaleryl chloride (6.8 mmol, 4 eq) was added, according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 3 h and allowed to warm to rt until completion, as indicatedby LC-MS. The solvent was removed in vacuuo, and the crude amide wasused directly for further transformation.

The crude amide described above (˜3.7 mmol) was suspended in acetic acid(10 mL), and ammonium acetate (excess, ˜30 eq) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 120° C. for 20h (as monitored by TLC and LC-MS). The reaction mixture was then cooledto rt and neutralized with saturated sodium bicarbonate and solid sodiumcarbonate. The resulting mixture was extracted with EtOAc (4×100 mL).The combined EtOAc extracts were washed with H₂O (2×60 mL) and brine(2×60 mL), and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuuo, and the crude product was purified by silica gelcolumn chromatography eluting with 10-20% EtOAc in hexane (overall yieldfrom the alkylated aniline: 62%).

The product (2.9 mmol) obtained above was dissolved in MeOH (50 mL) andhydrogenated in the presence of 10% Pd/C (0.5 g) until completion asindicated by LC-MS (˜2 h), according to General Procedure H. Thereaction mixture was then filtered to remove the catalyst. The solventwas removed in vacuuo to afford the desired 1-(4′-hydroxyphenyl)imidazole, which was used directly for further transformation withoutpurification (yield: 100%).

To a stirred solution of ice-cold3-dimethylamino-2,2-dimethyl-1-propanol (1 mmol) and TEA (1.5 mmol)dissolved in anhydrous DCM (8 mmol) was added dropwise methanesulfonylchloride (1.05 mmol), and the reaction mixture was stirred for 2 h at 0°C. and followed by additional 1 h at rt. After the removal of thesolvents in vacuuo, the crude mesylate was dissolved in DMF (10 mL).1-(4′-hydroxyphenyl) imidazole (0.5 mmol) obtained above and cesiumcarbonate (3 mmol) were added, and the mixture was heated with stirringat 90° C. for 3 h (monitored by LC-MS). After cooling to rt, thereaction was quenched with saturated sodium bicarbonate (20 mL), and theresulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAcextracts were washed with brine (3×30 mL), and dried over anhydroussodium sulfate. The solvent was removed in vacuuo, and the pure productwas obtained by silica gel column chromatography eluting with 5-10% MeOHin EtOAc (yield 252 mg).

MS m/z 672 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.70 (t, 3H), 0.83 (d, 6H), 1.03 (s, 6H), 1.13(m, 2H), 1.28 (m, 2H), 1.96 (m, 1H), 2.29 (s, 6H), 2.31 (s, 2H), 2.36(d, 2H), 2.47-2.56 (m, 4H), 3.77 (s, 2H), 3.91 (t, 2H), 4.26 (t, 1H),6.86 (d, 2H), 7.00 (d, 2H), 7.11 (d, 2H), 7.19-7.28 (m, 10H), 7.56 (d,2H) ppm

Example 499[3-(4-{4-[4-(3,3-diphenyl-propoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine(1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added,followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone(2.5 mmol). The reaction mixture was stirred under nitrogen at rt untilcompletion, as indicated by HPLC. The reaction mixture was then dilutedwith cold H₂O and the product was isolated in Et₂O. The combined organiclayers were washed with brine and dried over sodium sulfate. Evaporationof solvent in vacuuo afforded the desired product. The crude alkylatedaniline was purified by chromatography (Silica gel). Pure product wasobtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added,followed by slow addition of isovaleryl chloride (5.0 eq), according toGeneral Procedure R3. The reaction mixture was stirred under nitrogen at0° C. for 1 h and allowed to warm to ambient temperature untilcompletion, as indicated by HPLC. The solvent was removed in vacuuo, andthe crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in aceticacid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according toGeneral Procedure R4. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was then cooled down and neutralizedwith saturated sodium bicarbonate solution. Usual extractive work upwith EtOAc gave the cyclized product, (crude ˜80%) which was taken tothe next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was addedand the heterogeneous mixture was stirred overnight under H₂ atmosphereusing a balloon, according to General Procedure T2. The Pd/C was removedby filtration. The solvent was removed in vacuuo, and the crude4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenolwas used for further transformation without purification.

A stirred solution of the4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol(1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride(60% dispersion in oil; 1.0 mmol) in portions. The mesylate of3,3-diphenylpropan-1-ol (1.1 eq) was added to the reaction mixture, andstirred at it overnight, according to General Procedure T3. Et₂O (30 mL)was added to the reaction mixture followed by H₂O (10 mL). The organiclayer was washed with H₂O (2×15 mL) and brine, and dried over sodiumsulfate. The solvent was removed in vacuuo. Pure imidazole was obtainedfrom chromatography with 5-10% MeOH/DCM (yield 73 mg).

MS m/z 616 (M+H)⁺:

¹H NMR (CDCl₃): δ7.67 (d, 2H), 7.15-7.3, (m, 12H), 7.09 (s, 1H), 6.96(d, 2H), 6.84 (d, 2H), 4.25 (t, 1H), 4.07 (t, 2H), 3.9 (t, 2H), 3.74 (t,1H), 2.46-2.75 (m, 10H), 2.0 (m, 3H), 1.0 (t, 6H), 0.84 (d, 6H) ppm.

Example 5007-{2-butyl-4-[4-(4-chloro-phenoxy)-naphthalen-1-yl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride 7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (8.2g, 42% yield) was prepared by slightly modifying the published procedure(J. Med. Chem., 1997, 40, 3997-4005).

Di-tert-butyl dicarbonate (7.5 g, 33.8 mmol) was added to a solution of7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.8 g, 16.9 mmol),Et₃N (9.42 mL, 67.6 mmol) and DMAP (0.1 g) dissolved in anhydrous THF(60 mL). After being stirred overnight at rt, the reaction mixture wastreated with saturated NaHCO₃ (50 mL), and the resulting mixture wasextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine and dried (Na₂SO₄). The crude products were purified by flashchromatography (eluting with 10-20% EtOAc in hexanes) to give2-BOC-7-nitro-1,2,3,4-tetrahydroisoquinoline (4.1 g).

The nitro compound obtained above (4.1 g, 14.7 mmol) was dissolved inMeOH (80 mL) and hydrogenated in the presence of 10% Pd/C (0.3 g),according to General Procedure H. Workup afforded afforded7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline (2-Boc-TIQ aniline (3.6 g,98% yield) as a light-brown solid.

4′-(4-chlorophenoxy)-1′-acetonaphthone was prepared from4′-fluoro-1′acetonaphthone and 4-chlorophenol following generalprocedure Q2. 4′-(4-chlorophenoxy)-1′-acetonaphthone was brominatedfollowing general procedure R1. The bromo ketone was condensed with7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedureR2. The aminoketone intermediate was treated with n-pentanoyl chlorideaccording to general procedure R3. The product amide was then subjectedto imidazole formation employing general procedure R4. The BOC group ofthe product was removed employing general procedure T1 to afford7-{2-Butyl-4-[4-(4-chloro-phenoxy)-naphthalen-1-yl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride.

LC-MS (m/z): 508 (M+H)⁺.

Example 5012-biphenyl-4-yl-N-{-4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenyl}-acetamidehydrochloride

4-Nitrophenacyl bromide (5 mmol) was added to a stirred mixture of2-BOC-7-nitro-1,2,3,4-tetrahydroisoquinoline (5 mmol) in DCM (20 mL) atrt, and the mixture was stirred at rt overnight. The reaction mixturewas treated with sat. NaHCO₃ (30 mL), the resulting mixture wasextracted with EtOAc (200 mL), washed with brine and dried. The crudeproduct was purified by silica gel column chromatography (eluting with8% EtOAc in hexane to give the amino ketone intermediate (0.33 g).

Following the general procedures R2, R3, and R4 as for Example 500, theamino ketone intermediate (330 mg, 0.8 mmol) was converted into a4-nitrophenyl-substituted imidazole. The imidazole was reduced byPd-carbon catalytic hydrogenation following general procedure H to thecorresponding 4-aminophenyl imidazole.

PS-carbodiimide (1.27 mmol/g, 310 mg, 0.4 mmol) was added to a mixtureof the 4-aminophenyl imidazole obtained above (45 mg, 0.1 mmol) andbiphenylacetic acid (43 mg, 0.2 mmol) in anhydrous DCM (6 mL), and themixture was slowly shaken at rt overnight. The pure product (25 mg, 40%yield) was obtained after silica gel column chromatography (20% EtOAc inhexane).2-Biphenyl-4-yl-N-{4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenyl}-acetamidehydrochloride (20 mg) was obtained by treating the product with 4Nhydrogen chloride in dioxane solution, following the General ProcedureT1.

LC-MS (m/z): 541 (M+1)⁺.

Example 5027-{2-butyl-4-[4-(2,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride

1-[4-(2,4-Dichlorophenoxy)phenyl]ethan-1-one (282 mg, 1 mmol) wasbrominated by General Procedure R1. The bromo ketone was condensed with7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedureR2. The aminoketone intermediate was treated with n-pentanoyl chlorideaccording to General Procedure R3. The product amide was then subjectedto imidazole formation employing general procedure R4. The BOC group ofthe product was removed employing general procedure T1 to afford7-{2-butyl-4-[4-(2,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride (150 mg).

LC-MS (m/z): 493 (M+1)⁺.

Example 5037-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride

1-[4-(4-chlorophenylethoxy)]ethan-1-one (1 mmol) was brominated byGeneral Procedure R1. The bromo ketone was condensed with7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedureR2. The aminoketone intermediate was treated with n-pentanoyl chlorideaccording to General Procedure R3. The product amide was then subjectedto imidazole formation employing general procedure R4. The BOC group ofthe product was removed employing general procedure T1 to afford7-(2-Butyl-4-[(4-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-2-isobutyl-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride (145 mg).

LC-MS (m/z): 486 (M+H)⁺.

Example 5047-[4-(4-benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride

4-benzyloxyacetophone was brominated by General Procedure R1. The bromoketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinolinefollowing general procedure R2. The aminoketone intermediate was treatedwith n-pentanoyl chloride according to General Procedure R3. The productamide was then subjected to imidazole formation employing generalprocedure R4 to afford7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline.The BOC group of the product was removed employing general procedure T1to afford7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride (170 mg).

LC-MS (m/z): 438 (M+1)⁺.

Example 5059-(2-{-4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenoxy}-ethyl-9H-carbazolehydrochloride

7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinolinewas debenzylated according to General Procedure T2 to afford7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline.The phenol was condensed with the mesylate of 9H-carbazole-9-ethanolfollowing general procedure T3 to afford the ethylcarbazole etherintermediate. This ethylcarbazole intermediate was deprotected employinggeneral procedure T1 to afford9-(2-{-4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenoxy}-ethyl-9H-carbazolehydrochloride (55 mg).

LC-MS (m/z): 541 (M+1)⁺.

Example 5067-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride

1-[4-(4-methoxyphenoxy)phenyl]ethan-1-one (1 mmol) was brominated byGeneral Procedure R1. The bromo ketone was condensed with7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedureR2. The aminoketone intermediate was treated with n-pentanoyl chlorideaccording to General Procedure R3. The product amide was then subjectedto imidazole formation employing general procedure R4. The BOC group ofthe product was removed employing general procedure T1 to afford7-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride (yield 135 mg)

LC-MS (m/z): 454 (M+1)⁺.

Example 5077-(2-butyl-4-{4-[2-(4-tert-butyl-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride

7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinolinewas condensed with the mesylate of 2-(4-t-butylphenyl)ethanol accordingto General Procedure T3 to afford the phenyl ether intermediate, whichwas deprotected according to general procedure T1 to afford7-(2-butyl-4-{4-[2-(4-tert-butyl-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride (35 mg).

LC-MS (m/z): 508 (M+1)⁺.

Example 5087-{2-butyl-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride

7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinolinewas condensed with 2-(bromomethyl)naphthalene according to generalprocedure T3 to afford the phenyl ether intermediate, which wasdeprotected according to general procedure T1 to afford7-{2-butyl-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride (32 mg).

LC-MS (m/z): 488 (M+1)⁺.

Example 5097-{2-butyl-4-[4-(4-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride

7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinolinewas condensed with 4-trifluoromethylbenzyl bromide according to generalprocedure T3 to afford the phenyl ether intermediate, which wasdeprotected according to general procedure T1 to afford77-{2-butyl-4-[4-(4-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinolinehydrochloride (45 mg).

LC-MS (m/z): 506 (M+1)⁺.

Example 5107-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride

1-[4-(4-chlorophenylethoxy)]ethan-1-one (1 mmol) was brominated byGeneral Procedure R1. The bromo ketone was condensed with7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedureR2. The aminoketone intermediate was treated with n-pentanoyl chlorideaccording to General Procedure R3. The product amide was then subjectedto imidazole formation employing general procedure R4. The BOC group ofthe product was removed employing general procedure T1 to afford7-(2-Butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride (170 mg).

LC-MS (m/z): 486 (M+1)⁺.

Example 511[3-(4-{2-(4-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

Example 511 was synthesized by the method established for Example 406,using 4-butylcyclohexanecarbonyl chloride in place of valeryl chloride(yield 300 mg).

MS: m/z 614 (M+H)⁺

Example 5122-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine

Example 512 was synthesized by the method established for Example 464,utilizing N—BOC-ethanolamine in phase of 3-dimethylamino-1-propanol toproduce2-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylaminotert-butyl carbamate as an intermediate. This intermediate wasdeprotected employing general procedure T1 to afford Example 512 as thehydrochloride salt. (Yield: 115 mg).

MS: m/z 462 (M+H)⁺

Example 513[3-(4-{2-(trans-4-tert-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

Example 513 was prepared by chromatographic purification on silica gelof the compound of Example 486. 500 mg of Example 486 was separated bysilica gel column chromatography, eluting with 5-10% MeOH in DCM, togive the cis-isomer (120 mg) followed by trans-isomer Example 513 (200mg).

¹H NMR (400 MHz, CDCl₃): δ 0.82 (s, 9H), 1.08 (t, 6H), 1.50-2.50 (m,12H), 2.66 (q, 4H), 2.73 (t, 2H), 4.02 (t, 2H), 6.89 (d, 2H), 7.04 (d,2H), 7.07 (d, 2H), 7.08 (s, 1H), 7.27 (d, 2H), 7.36 (d, 2H), 7.69 (d,2H) ppm

MS: m/z 614 (M+H)⁺

Example 514[3-(4-{2-(cis-4-tert-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

Example 514 was prepared by chromatographic purification on silica gelof the compound of Example 486. 500 mg of Example 486 was separated bysilica gel column chromatography, eluting with 5-10% MeOH in DCM, togive the cis-isomer Example 514 (120 mg) followed by trans-isomer (200mg).

MS: m/z 614 (M+H)⁺

Example 515[2-(4-{2-Butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

A mixture of 4-chloropyridine hydrochloride salt (15.0 g) and2-methylaminoethanol (30 mL) was refluxed for 48 hour. After cooling tort the crude mixture was added slowly to saturated solution of sodiumbicarbonate (150 mL). The product was extracted with EtOAc (3×100 mL),the combined EtOAc was washed with brine (50 mL), dried (Na₂SO₄) andremoved in vacuo to give the desired product2-[methyl(pyridin-4-yl)amino]ethanol as yellow solid (7.0 g).

2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate was preparedaccording to general procedure P2.

4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazole-4-yl}-phenolwas prepared via a modification of the procedure employed to synthesize{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol.

Sodium hydride (50.0 mg, 60% dispersion in oil) was added to a mixtureof 100 mg of4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazole-4-yl}-phenoland 200 mg 2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate in DMF (5mL). After 24 h of stirring at rt, the mixture was added to ether (50mL) and the ether was washed with water and dried (Na₂SO₄). The solventwas removed in vacuo. Silica gel chromatography afforded 150 mg ofExample 515.

MS: m/z 605 (M+H)⁺

Example 516[2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

4-{1-[4-(4-fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenolwas prepared in analogous fashion to4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenol.Alkylation of the phenol proceeded as for Example 515 to afford Example516 (47 mg).

MS: m/z 537 (M+H)⁺

¹H NMR (CDCl₃): δ 8.23 (d, 2H), 7.70 (d, 2H), 7.53 (d, 2H,), 7.24 (s,1H), 7.12 (d, 2H), 7.07 (m, 2H), 7.04 (d, 2H), 6.87 (d, 2H), 6.58 (d,2H) 4.17 (t, 2H), 3.81 (t, 2H), 3.11 (s, 3H), 2.54 (d, 2H), 2.06 (m,1H), 0.87 (d, 6H) ppm

Example 517[2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-(3-methyl-pyridin-4-yl)-amine

Example 517 was prepared in analogous fashion to Example 516, with theuse of 3-methyl-4-chloropyridine in place of 4-chloropyridine. (Yield:110 mg)

MS: m/z 551 (M+H)⁺

Example 518[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-ethyl-pyridin-4-yl-amine

2-[Ethyl(pyridin-4-yl)amino]ethanol was synthesized via an analogousmethod as that employed for 2-[methyl(pyridin-4-yl)amino]ethanol.

2-[Ethyl(pyridin-4-yl)amino]ethanol was converted to themethanesulfonate via a modification of General Procedure P2.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol wassynthesized by an analogous series of procedures as for Example 77.

Another procedure was below;

4-Acetoxyacetophenone (10.7 g, 60 mmol) in dioxane (200 mL) was treatedwith pyridinium hydrotribromide (21 g, 66 mmol, 1.1 eq) added inportions at rt, according to General Procedure R1. The reaction mixturewas stirred at rt for 6 h. The reaction was quenched by adding cold H₂O(100 mL), and extracted with ether (4×100 mL). The ethereal solution waswashed with H₂O (100 mL) and dried (anhydrous Na₂SO₄). The solvent wasthen removed in vacuo and the α-bromoacetophenone obtained above wasadded to a stirred solution of 4-(4′-chlorophenoxy)aniline (13.2 g, 60mmol, 1.1 eq) and anhydrous DMF (100 mL) at rt, and the mixture wasstirred at the same temperature for 5 h (monitored by LC-MS). Thereaction mixture was treated with sat. NaHCO₃ (100 mL), and theresulting mixture was extracted with EtOAc (4×100 mL). The combinedEtOAc extracts were washed with H₂O (2×100 mL) and brine (2×100 mL), anddried (Na₂SO₄).

The solvent was removed in vacuo, and the alkylated aniline was used fornext step To a stirred solution of the c alkylated aniline dissolved inanhydrous DCM (250 mL) at 0° C., triethylamine (15.2 mL, 180 mmol) wasadded, followed by slow addition of isovaleryl chloride (14.7 mL, 120mmol), according to General Procedure R3. The reaction mixture wasstirred under N₂ at 0° C. for 0.5 h and then at rt for another 2 h (ormonitored by LC-MS). The solvent was removed in vacuo, and the crudeamide was used directly for further transformation.

To a stirred suspension of the amide described above in AcOH (30 mL),ammonium acetate (80 g) was added, according to General Procedure R4.The reaction mixture was stirred at 100° C. for 2 h (as monitored byLC-MS). The reaction mixture was then cooled down and neutralized withsat. NaHCO₃ (100 mL) and solid Na₂CO₃. The resulting mixture wasextracted with EtOAc (4×150 mL) and the organic phase was concentrated.The light-yellow solid product was collected after filtration. Thefiltrate was concentrated in vacuo to about 150 mL volume and afterstanding at rt the solid product was collected and dried, overall yield11 g of{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol.

Sodium hydride (50.0 mg, 60% dispersion in oil) was added to mixture of100 mg of4-[1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl]phenoland 180 mg of 2-[ethyl(pyridin-4-yl)amino]ethyl methanesulfonate in DMF(5 mL). After 24 h of stirring at rt, the mixture was added to ether (50mL) and washed with water and dried (Na₂SO₄). The solvent was removed invacuo. Chromatography on silica gel afforded Example 518 (36 mg).

MS: m/z 567 (M+H)⁺

Example 519[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-pyridin-4-yl-amine

2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine,the product of Example 512, was treated with 4-chloropyridine in DMF andwas heated at 100° C. Aqueous workup and chromatography on silica gelafforded Example 519. (Yield: 80 mg)

MS: m/z 539 (M+H)⁺

Example 520[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-bis-pyridin-2-ylmethyl-amine

The methanesulfonate of N-Boc-glycinol was synthesized by modifying thegeneral procedure P2.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (2mmol) was added to a solution of Cs₂CO₃ (10 eq., 20 mmol) in anhydrousDMF (5 ml). This was followed by addition of the mesylate obtained aboveand the reaction mixture was heated to 90° C. for 2-3 h. The reactionmixture was then cooled to rt, diluted with cold water and the productwas extracted with DCM. The organic layer was dried over anhydroussodium sulfate and concentrated in vacuo to give desired product, whichwas BOC-deprotected according to general procedure T1. The HCl salt wasdissolved in water, neutralized with 4N NaOH solution and the crudeproduct was extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo to give desiredproduct amine.

The crude product obtained above was taken in anhydrous DCM (5 ml).2-pyridylcarboxaldehyde (2.5 eq.) and Na(OAc)₃BH (2.5 eq.) was added tothis solution and the reaction mixture was stirred at it for 2-3 h. Theproduct was concentrated in vacuo and extracted with EtOAc and theorganic layer was washed with saturated sodium bicarbonate solution. Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo to give desired product, Example 520 (yield 96 mg).

MS: m/z 644 (M+H)⁺

Example 521N-[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-guanidine

2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine,the product of Example 512, was treated in acetonitile with DIEA andN,N′-bis-BOC-1-guanylpyrazole. The resulting mixture was then refluxed.The reaction mixture was then cooled to rt and diluted with EtOAc. Themixture was washed with water and brine and dried over anhydrous sodiumsulfate. Solvent was removed in vacuo and the residue obtained waspurified by silica gel column chromatography to afford the BOC-protectedguanadino intermediate. The BOC-protected guanadino intermediate wastreated with 4M HCl/dioxane to remove the BOC group as described ingeneral procedure T1, affording Example 521.

MS: m/z 504 (M+H)⁺

Example 5222-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-1-(4-pyridin-4-yl-piperazin-1-O-ethanone

To a stirred solution of 4-pyridyl-piperazine (2 mmol) in DCM (4 mL) at0° C., triethylamine (6.0 mmol) was added followed by addition of2-chloroacetyl chloride (4 mmol). The reaction mixture was stirred undernitrogen at rt until completion, as indicated by TLC or HPLC. Thereaction mixture was treated with saturated aqueous sodium bicarbonatesolution (5 mL), then extracted with EtOAc (2×15 mL). The combinedorganic layers were washed with H₂O (2×15 mL) and brine, and dried oversodium sulfate. Evaporation of the solvent in vacuo afforded the amide.The crude product was used for further transformation.

To the above amide (2 mmol) in DMF (5 ml) was added Cesium carbonate (10mmol, 5 eq), followed by the addition of{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (1.5mmol) and the reaction was heated to 90° C. until completion, asindicated by TLC or HPLC. After cooling to rt, the reaction mixture wastreated with saturated sodium bicarbonate (150 ml). The aqueous layerwas extracted with EtOAc (4×100 ml). The organic layer was washed withwater (2×10 ml) and brine (15 ml). The organic layer was dried overmagnesium sulfate, and the solvent was removed in vacuo to afford thedesired imidazole which was purified by was purified by chromatographyover silica gel to afford Example 522.

MS: m/z 622 (M+H)⁺

Example 5235-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxymethyl)-pyrrolidin-3-ol

Sodium borohydride (227 mg, 6 mmol) was added at 0° C. to a stirredsolution of (2S,4R)—N—BOC-4-(t-butyldimethylsilyloxy)prolinaldehyde (522mg, 1.58 mmol) in MeOH (10 mL), and the mixture was stirred at rt for 3h. The reaction was quenched by adding sat. NaHCO₃ (20 mL), and theresulting mixture was extracted with EtOAc (3×50 mL). The EtOAc extractswere washed with brine (2×50 mL), and dried (Na₂SO₄). The solvent wasremoved in vacuo to give(2S,4R)—N—BOC-4-(t-butyldimethylsilylhydroxy)prolinol (550 mg).

The alcohol obtained above was converted to the methanesulfonateaccording to general procedure P2.

4-{1-[4-Chlorophenoxy)phenyl]-2-isobutyl-1H-imidazol-4-yl}phenoldescribed above (840 mg, 2 mmol) was added to a stirred mixture of themesylate obtained in the previous step, Cs₂CO₃ (1.95 g, 6 mmol) inanhydrous DMF (20 mL), and the mixture was heated with stirring at 90°C. for 15 h. The reaction was quenched by adding sat. NaHCO₃ and theresulting mixture was extracted with EtOAc. The EtOAc extracts werewashed with brine and dried (Na₂SO₄). The solvent was removed in vacuoto give crude alkylated product.

2N hydrogen chloride in ethereal solution (2 mL) was added to a stirredmixture of the alkylated imidazole obtained above (150 mg) in DCM (8 mL)at rt. After being stirred at rt for 4 h, the reaction mixture wastreated with sat. NaHCO₃. The resulting mixture was extracted withEtOAc. The EtOAc extracts were washed with brine and dried (Na₂SO₄). Thesolvent was removed in vacuo, and the residue was purified by silica gelcolumn chromatography to give5-(4-{1-[4-(4-chlorophenoxy)phenyl]-2-isobutyl-1H-imidazol-4-yl}phenoxymethyl)pyrrolidin-3-ol(50 mg).

LC-MS: m/z 518 (M+H)⁺

1H NMR (400 MHz, CDCl₃): δ 0.84 (d, 6H), 1.25-3.20 (m, 6H), 2.53 (d,2H), 4.05 (m, 3H), 4.50 (m, 1H), 6.91 (d, 2H), 7.01 (d, 2H), 7.05 (d,2H), 7.10 (s, 1H), 7.24 (d, 2H), 7.34 (d, 2H), 7.66 (d, 2H) ppm.

Example 5243-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-pyridin-4-ylamine

To an ice-cold solution of 3-bromopyridine-N-oxide (4 mmol) inconcentrated H₂SO₄ (4 ml), concentrated HNO₃ (0.5 ml) was addedgradually. The reaction mixture was heated at 90° C. for 48 h. Thereaction mixture was then cooled to rt, diluted with cold water and theproduct was extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo to give desiredproduct, 3-bromo-4-nitropyridine N-oxide.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (1.1eq. 4.4 mmol) was added slowly to a solution of NaH (8 mmol) inanhydrous DMF (6 ml) at 0° C. This was followed by addition of3-bromo-4-nitropyridine-N-oxide (4 mmol) and the reaction mixture washeated to 90° C. for 2-3 h or until the completion of reaction. Thereaction mixture was then cooled to rt, diluted with cold water and theproduct was extracted with DCM. The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo to give desiredproduct, which was taken up in acetic acid (4 ml). Powdered iron (2 eq.,8 mmol) was added and the reaction was heated to 90° C. for 2-3 h. Thereaction mixture was then cooled to rt, diluted with cold water and theproduct was extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo to give desiredproduct, Example 524. (Yield: 60 mg)

MS: m/z 495 (M+1)⁺

Example 525(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-pyridin-4-yl-amine

[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-aniline wassynthesized by procedures analogous to those for the similar4-(4-aminophenyl)1H-imidazole intermediate in the preparation of Example501.

A mixture of 200 mg of4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}aniline(200 mg, 0.47 mmole), 4-chloropyridine hydrochloride (0.5 g, 3.2 mmole)and potassium carbonate (0.5 g, 3.6 mmole) were heated at 100° C. in DMF(10 mL) for 24 h. After cooling to rt the mixture was diluted withether, washed with water) and dried (Na₂SO₄). Silica gel chromatographyof the crude material afforded Example 525 (50 mg).

MS: m/z 495 (M+H)⁺

Example 5262-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxymethyl)-3,5-dimethyl-pyridin-4-ylamine

(3,5-dimethyl-4-nitro-2-pyridyl)methyl mesylate was synthesized by thegeneral procedure P2.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (2mmol) was added to a solution of Cs₂CO₃ (10 eq., 20 mmol) in anhydrousDMF (5 ml). This was followed by addition of the mesylate obtained aboveand the reaction mixture was heated to 90° C. for 2-3 h. The reactionmixture was then cooled to rt, diluted with cold water and the productwas extracted with DCM. The organic layer was dried over anhydroussodium sulfate and concentrated in vacuo to give desired phenyl ether.

The crude product obtained above was taken in acetic acid (5 ml).Powdered iron (2 eq., 8 mmol) was added to the reaction mixture and thereaction was heated to 90° C. for 2-3 h or until the completion ofreaction. The reaction mixture was then cooled to rt, diluted with coldwater and the product was extracted with EtOAc. The organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuo to givedesired product. Example 526. (Yield: 80 mg)

MS: m/z 537 (M+H)⁺

Example 5271-[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-4-pyridin-4-yl-piperazine

The product of Example 522 was taken in 4 ml of THF to which was added 5eq. of BH3-THF solution and the reaction was heated to reflux until thereaction was complete. The crude product was purified by silica gelchromatography to afford Example 527.

MS: m/z 608 (M+H)⁺

Example 5284-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenylamine

Example 528 was prepared by modifying the procedures utilized in thesynthesis of Example 493, with utilization of4-tert-butoxycarbonylaminophenol in place of 4-acetamidophenol. The BOCgroup was removed from the intermediate utilizing general procedure T1to afford the product, Example 528, as the HCl salt.

MS: m/z 513 (M+H)⁺

Example 529{3-[4-(2-Butyl-4-dibenzofuran-2-yl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

A solution of dibenzofuran (0.5 mmol) in anhydrous DCM was cooled to 0°C. AlCl₃ (1.5 eq., 0.75 mmol) was added followed by a slow addition ofacetyl chloride (1.5 eq., 0.75 mmol). The reaction mixture was stirredat 0° C. for 2-3 h or until the completion of reaction. The product wasextracted with DCM and washed with saturated sodium bicarbonatesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give dibenzofuran-2-ylethan-2-one.

Example 529 was prepared by modifying the procedures utilized for thesynthesis of Example 463, utilizing dibenzofuran-2-ylethan-2-one as thearyl ketone starting material. (Yield: 75 mg)

MS: m/z 496 (M+H)⁺

Example 530N-[4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]-benzamide

Example 530 was prepared by modifying the procedures utilized in thesynthesis of Example 493, with utilization of4-(tert-butoxycarbonylamino)phenol in place of 4-acetamidophenol. TheBOC group was removed from the intermediate utilizing general procedureT1 to afford the product, Example 528, as the HCl salt. The product wastreated with benzoyl chloride and TEA in DCM to afford, after aqueousworkup and purification by silica gel chromatography, Example 530.

MS: m/z 617 (M+H)⁺

Example 531N-[4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]-isonicotinamide

Example 530 was prepared by modifying the procedures utilized in thesynthesis of Example 493, with utilization of4-(tert-butoxycarbonylamino)phenol in place of 4-acetamidophenol. TheBOC group was removed from the intermediate utilizing general procedureT1 to afford the product, Example 528, as the HCl salt. The product wastreated with 4-pyridylcarbonyl chloride and TEA in DCM to afford, afteraqueous workup and purification by silica gel chromatography, Example531.

MS: m/z 618 (M+H)⁺

Example 532[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

A mixture of 4-chloropyridine hydrochloride salt (15.0 g) and2-methylaminoethanol (30 mL) was refluxed for 48 hour. After cooling tort the crude mixture was added slowly to saturated solution of sodiumbicarbonate (150 mL). The product was extracted with EtOAc (3×100 mL),the combined EtOAc was washed with brine (50 mL), dried (Na₂SO₄) andremoved in vacuo to give the desired product2-[methyl(pyridin-4-yl)amino]ethanol as yellow solid (7.0 g).

2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate was synthesized asdescribed for Example 515.

Sodium hydride (50.0 mg, 60% dispersion in oil) was added to mixture of150 mg of4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenoland 2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate (75 mg) in DMF(5 mL). After 24 h of stirring at rt, the mixture was added to ether (50mL) and the organic phase was washed with water and dried (Na₂SO₄). Thesolvent was removed in vacuo and the product purified by silica gelchromatography to afford 80 mg of Example 532.

MS: m/z 553 (M+H)⁺

Example 533N-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-2-dimethylamino-acetamide

1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-4-(4-nitrophenyl)-1H-imidazolewas synthesized following the general procedures utilized in example501. The nitro group was reduced according to general procedure H toafford1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-4-(4-aminophenyl)-1H-imidazole,which was coupled with N,N-dimethylglycine using PS-carbodiimideaccording to the procedure utilized in Example 502 to afford Example533.

MS: m/z 503 (M+H)⁺

Example 534{3-[4-(4-{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

Example 534 was synthesized by modification of the procedures utilizedfor the synthesis of example 459. 3,3(4-chlorophenyl)-2-propene-1-ol wasconverted to the methanesulfonate and utilized in condensation with4′-hydroxyacetophenone. Isovaleryl chloride was utilized in place ofbenzyloxyacetyl chloride (yield 35 mg).

MS: m/z 682 (M+H)⁺

Example 535{3-[4-(4-{4-[3,3-Bis-(4-fluoro-phenyl)-propoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

The intermediate phenol4-(4-hydroxyphenyl)-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amineutilized in the synthesis of Example 477 was condensed with themethanesulfonate of 3,3(4-fluorophenyl)-1-propanol (synthesizedaccording to general procedure P2). The condensation was conducted inaccord with similar operation in the preparation of Example 477 toprovide Example 535.

MS: m/z 652 (M+H)⁺

Example 536[2-(4-{4-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

4-Fluoronitrobenzene was condensed with2-[methyl(pyridin-4-yl)amino]ethanol according to general procedure Cand the nitro group was then reduced according to general procedure H toafford the aniline intermediate. This aniline was utilized inmodification of the procedure for preparation of Example 485 to affordExample 536.

MS: m/z 553 (M+H)⁺

Example 537[3-(4-{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(1-methyl-pyridin-3-yl)-ethyl]-imidazol-1-yl}phenoxy)-propyl]-diethylmethylaminonium iodide

{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(pyridin-3-yl)-ethyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-aminewas synthesized modifying the procedures utilized in the preparation ofExample 485, where 3-(3-pyridyl)-propionyl chloride was utilized inplace of valeryl chloride. The product{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(pyridin-3-yl)-ethyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-aminewas treated with excess methyl iodide, concentrated in vacuo, and thesolid collected to afford the product, Example 537 (Yield: 37 mg)

MS: m/z 625 (M+H)⁺

Example 538[3-(4-{2-(N—BOC-piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

The procedure utilized for the preparation of Example 486 was modified,employing N—BOC-piperidine-4-acetic acid in place of4-tert-butylcyclohexanecarboxylic acid, to afford 270 mg of Example 538.

MS: m/z 673 (M+H)⁺

Example 539[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

The compound of Example 538 was deprotected according to GeneralProcedure T1 to afford 116 mg of Example 539 as the HCl salt.

MS: m/z 573 (M+H)⁺

Example 540[3-(4-{2-(N-ethyl-piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine(Example 539) (0.1 mmol) was treated in anhydrous DCM (2 ml) withacetaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.).The reaction mixture was stirred at it Crude product was extracted intoEtOAc and washed with saturated sodium bicarbonate solution. The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuoto give desired product, which was purified by column chromatography onsilica gel to afford 49 mg of Example 540.

MS: m/z 601 (M+H)⁺

Example 541[3-(4-{2-(piperidine-4-ylmethyl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The procedure of Example 485 was adapted, using4-BOC-piperidine-1-acetic acid in place of valeryl chloride. Theresulting imidazole was deprotected using General Procedure T1 to affordExample 541 (48 mg) as the HCl salt.

MS: m/z 602 (M+H)⁺

Example 542[3-(4-{2-(N-ethylpiperidine-4-ylmethyl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 541 was treated in anhydrous DCM (2 ml) withacetaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.).The reaction mixture was stirred at rt. Crude product was extracted intoEtOAc and washed with saturated sodium bicarbonate solution. The organiclayer was dried over anhydrous sodium sulfate and concenterated in vacuoto give desired product, which was purified by column chromatography onsilica gel to afford 50 mg of Example 542.

¹H NMR: δ 7.68 (d, 2H), 7.23 (m, 6H), 7.16 (s, 1H), 6.95 (m, 2H), 6.88(d, 2H), 4.17 (t, 2H), 4.06 (t, 2H), 3.06 (t, 2H), 2.91 (d, 2H), 2.81(broad, 1H), 2.57 (m, 6H), 2.43 (m, 6H), 1.95-2.05 (m, 6H), 1.09 (t, 9H)ppm

MS: m/z 629 (M+H)⁺

Example 543[3-(4-{2-(N-acetylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The procedure of Example 485 was adapted, using4-acetyl-piperidine-1-carbonyl chloride in place of valeryl chloride, toafford Example 543 (40 mg).

MS: m/z 629 (M+H)⁺

Example 544[3-(4-{2-(piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

Example 543 (1 mmol, 125 mg) was taken in 6 N HCl (5 ml) and thereaction was refluxed. The reaction mixture was then cooled to rt,diluted with water and neutralized with 3N NaOH solution. Product wasextracted with EtOAc and the organic layer was dried over anhydroussodium sulfate, concentrated in vacuo to give crude product, which waspurified by column chromatography on silica gel to afford 290 mg ofExample 544.

MS: m/z 587 (M+H)⁺

Example 545[3-(4-{2-(N-Benzylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) withbenzaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.).The reaction mixture was stirred at rt. Crude product was extracted intoEtOAc and washed with saturated sodium bicarbonate solution. The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuoto give desired product, which was purified by column chromatography onsilica gel to afford 50 mg of Example 545.

¹H NMR: δ 7.68 (d, 2H), 7.28 (d, 2H), 7.21-7.26 (m, 9H), 7.17 (s, 1H),6.97 (d, 2H), 6.87 (d, 2H), 4.16 (t, 2H), 4.07 (t, 2H), 3.48 (s, 2H),3.05 (t, 2H), 2.91 (broad, 1H), 2.74 (t, 2H), 2.66 (m, 8H), 2.05 (m,6H), 1.11 (t, 6H) ppm

MS: m/z 677 (M+H)⁺

Example 546[3-(4-{2-(N-(2-Pyridylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) withpyridine-2-carboxaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH(1.5 eq.). The reaction mixture was stirred at rt. Crude product wasextracted into EtOAc and washed with saturated sodium bicarbonatesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give desired product, which was purified bycolumn chromatography on silica gel to afford 40 mg of Example 546.

MS: m/z 678 (M+H)⁺

Example 547[3-(4-{2-(N-(2-Imidazolylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) withimidazole-2-carboxaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH(1.5 eq.). The reaction mixture was stirred at rt. Crude product wasextracted into EtOAc and washed with saturated sodium bicarbonatesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give desired product, which was purified bycolumn chromatography on silica gel to afford 40 mg of Example 547.

¹H NMR: δ 7.66 (d, 2H), 7.2-7.3 (m, 7H), 7.06 (s, 1H), 6.98 (m, 3H),6.88 (d, 2H), 4.18 (t, 2H), 4.05 (t, 2H), 3.65 (s, 2H), 3.08 (t, 2H),2.81 (broad, 1H), 2.75 (m, 2H), 2.55-2.65 (m, 8H), 1.95-2.08 (m, 6H),1.09 (t, 6H) ppm

MS: m/z 667 (M+H)⁺

Example 548[3-(4-{2-(N-(4-biphenyl)methylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with4-biphenylcarboxaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH(1.5 eq.). The reaction mixture was stirred at rt. Crude product wasextracted into EtOAc and washed with saturated sodium bicarbonatesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give desired product, which was purified bycolumn chromatography on silica gel to afford 45 mg of Example 548.

¹H NMR: δ 7.68 (d, 2H), 7.59 (d, 2H), 7.54 (d, 2H), 7.38-7.44 (m, 5H),7.19-7.29 (m, 6H), 7.09 (s, 1H), 6.79 (d, 2H), 6.88 (d, 2H), 4.18 (t,2H), 4.08 (t, 2H), 3.55 (s, 2H), 3.08 (t, 2H), 2.98 (broad, 1H), 2.65(t, 2H), 2.58-2.65 (m, 8H), 1.98-2.09 (m, 6H), 1.12 (t, 6H) ppm.

MS: m/z 753 (M+H)⁺

Example 549[3-(4-{2-(N-Cyclohexylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) withcyclopentanone (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.).The reaction mixture was stirred at rt. Crude product was extracted intoEtOAc and washed with saturated sodium bicarbonate solution. The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuoto give desired product, which was purified by column chromatography onsilica gel to afford 52 mg of Example 549.

¹H NMR: δ 7.68 (d, 2H), 7.38 (m, 3H), 7.21 (m, 3H), 7.08 (s, 1H), 6.98(m, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.08 (t, 2H), 3.08 (t, 2H), 2.67(t, 2H), 2.51-2.55 (m, 8H), 1.99-2.08 (m, 6H), 1.91 (broad, 4H), 1.68(broad 2H), 1.51 (broad 4H), 1.12 (t, 6H) ppm.

MS: m/z 655 (M+H)⁺

Example 550[3-(4-{2-(N-(4-Cyanobenzyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with4-cyanobenzaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5eq.). The reaction mixture was stirred at rt. Crude product wasextracted into EtOAc and washed with saturated sodium bicarbonatesolution. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give desired product, which was purified bycolumn chromatography on silica gel to afford 70 mg of Example 550.

¹H NMR: δ 7.69 (d, 2H), 7.59 (d, 2H), 7.44 (d, 2H), 7.2-7.3 (m, 6H),7.09 (s, 1H), 6.99 (d, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.09 (t, 2H),3.55 (s, 2H), 3.08 (t, 2H), 2.85 (broad, 1H), 2.5-2.8 (m, 10H), 1.9-2.1(m, 6H), 1.09 (t, 6H) ppm.

MS: m/z 702 (M+H)⁺

Example 551[3-(4-{2-(N-Ethylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) withacetaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.).The reaction mixture was stirred at rt. Crude product was extracted intoEtOAc and washed with saturated sodium bicarbonate solution. The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuoto give desired product, which was purified by column chromatography onsilica gel to afford 50 mg of Example 551.

¹H NMR: δ 7.68 (d, 2H), 7.23 (d, 2H), 7.22 (m, 4H), 7.16 (s, 1H), 6.95(d, 2H), 6.88 (d, 2H), 4.17 (t, 2H), 4.05 (t, 2H), 3.05-3.07 (m, 7H),2.51-2.61 (m, 6H), 2.39 (q, 2H), 1.89-2.09 (m, 6H), 1.12 (t, 9H) ppm.

MS: m/z 678 (M+H)⁺

Biological Assay

The following assay method is utilized to identify compounds of Formula(I) which are effective in binding with RAGE, and hence useful asmodulators, preferably antagonists of RAGE.

General Assay Procedure

S100b, β-amyloid and CML (500 ng/100 μL/well) in 100 mM sodiumbicarbonate/sodium carbonate buffer (pH 9.8) is loaded onto the wells ofa NUNC Maxisorp flat bottom 96-well microtitre plate. The plate isincubated at 4° C. overnight. The wells are aspirated and treated with50 mM imidazole buffer saline (pH 7.2) (with 5 mM CaCl₂/mgCl₂)containing 1% bovine serum albumin (BSA) (300 μL/well) for 1 h at RT.The wells are aspirated.

Test compounds are dissolved in nanopure water (concentration: 10-100μM). DMSO may be used as co-solvent. 25 μL of test compound solution in4% DMSO is added, along with 75 μL sRAGE (6.75 nM FAC) to each well andsamples are incubated for 1 h at 37° C. The wells are washed 4 timeswith 155 mM NaCl pH 7.2 buffer saline and are soaked 10 seconds betweeneach wash.

Non-radioactive detection is performed by adding:

10 μL Biotinylated goat F(ab′)2 Anti-mouse IgG. (8.0×10⁻⁴ mg/mL, FAC)

5 μL Alk-phos-Sterptavidin (3×10⁻³ mg/mL FAC)

0.42 μL per 5 mL Monoclonal antibody for sRAGE (FAC 6.0×10⁻³ mg/mL) to 5mL 50 mM imidazole buffer saline (pH 7.2) containing 0.2% bovine serumalbumin and 5 mM CaCl₂. The mixture is incubated for 30 minutes at RT.100 μL complex is added to each well and incubation is allowed toproceed at rt for 1 h. Wells are washed 4 times with wash buffer andsoaked 10 s between each wash. 100 μL1 mg/mL (pNPP) in 1 Mdiethanolamine (pH adjusted to 9.8 with HCl) is added. Color is allowedto develop in the dark for 30 min to 1 h at rt. The reaction is quenchedwith 10 μL of stop solution (0.5 N NaOH in 50% ethanol) and theabsorbance is measured spectrophotometrically with a microplate readerat 405 nm.

The Examples in Table 1 were tested according to the assay methoddescribed above, employing S100b as the RAGE ligand, and were found topossess IC₅₀ in the assay of less than 10 μM. IC₅₀ (μM) of ELISA assayrepresents the concentration of compound at which 50% signal has beeninhibited.

The invention further provides pharmaceutical compositions comprisingthe RAGE modulating compounds of the invention. The term “pharmaceuticalcomposition” is used herein to denote a composition that may beadministered to a mammalian host, e.g., orally, topically, parenterally,by inhalation spray, or rectally, in unit dosage formulations containingconventional non-toxic carriers, diluents, adjuvants, vehicles and thelike. The term “parenteral” as used herein, includes subcutaneousinjections, intravenous, intramuscular, intracisternal injection, or byinfusion techniques.

The pharmaceutical compositions containing a compound of the inventionmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous, or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, incorporated herein by reference, to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example aliquid paraffin, or a mixture thereof. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the invention. These compositions canbe prepared by mixing the drug with a suitable non-irritating excipientwhich is solid at ordinary temperatures but liquid at the rectaltemperature and will thus melt in the rectum to release the drug. Suchmaterials include cocoa butter and polyethylene glycols, for example.

For topical use, creams, ointments, jellies, solutions or suspensions,lotions, eye ointments and eye or ear drops, impregnated dressings andaerosols etc., containing the compounds of the invention arecontemplated. These topical formulations may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams. The formulations mayalso contain compatible conventional carriers, such as cream or ointmentbases and ethanol or oleyl alcohol for lotions. Such carriers may bepresent as from about 0.1% up to about 99% of the formulation. Moreusually they will form up to about 80% of the formulation. For thepurpose of this application, topical applications shall include mouthwashes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

The compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels. Also providedby the present invention are prodrugs of the invention.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

Pharmaceutically acceptable salts of the compounds of the presentinvention, where a basic or acidic group is present in the structure,are also included within the scope of the invention. The term“pharmaceutically acceptable salts” refers to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid or by reacting theacid with a suitable organic or inorganic base. Representative saltsinclude the following salts: Acetate, Benzenesulfonate, Benzoate,Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate,Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride,Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Methylbromide, Methyliodide, Methylchloride, Methylnitrate,Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide, Trimethylammonium and Valerate. When an acidic substituentis present, such as —COOH, there can be formed the ammonium,morpholinium, sodium, potassium, barium, calcium salt, and the like, foruse as the dosage form. When a basic group is present, such as amino ora basic heteroaryl radical, such as pyridyl, an acidic salt, such ashydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate,trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate,succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate,methiodide, methbromide, methchloride, methanesulfonate,ethanesulfonate, picrate and the like, and include acids related to thepharmaceutically-acceptable salts listed in the Journal ofPharmaceutical Science, 66, 2 (1977) p. 1-19.

Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of the invention and these form a furtheraspect of the invention.

In addition, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates are alsoencompassed within the scope of the invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, or prodrug thereof, and oneor more pharmaceutically acceptable carriers, excipients, or diluents.

The compounds of the present invention selectively act as modulators ofRAGE binding to a single endogenous ligand, i.e., selective modulatorsof β-amyloid-RAGE interaction, and therefore are especially advantageousin treatment of Alzheimer's disease and related dementias.

Further, the compounds of the present invention act as modulators ofRAGE interaction with two or more endogenous ligands in preference toothers. Such compounds are advantageous in treatment of related orunrelated pathologies mediated by RAGE, i.e., Alzheimer's disease andcancer.

Further, the compounds of the present invention act as modulators ofRAGE binding to each and every one of its ligands, thereby preventingthe generation of oxidative stress and activation of NF-κB regulatedgenes, such as the cytokines IL-1, and TNF-α. Thus, antagonizing thebinding of physiological ligands to RAGE prevent targetedpathophysiological consequences and useful for management or treatmentof diseases, i.e., AGE-RAGE interaction leading to diabeticcomplications, S100/EN-RAGE/calgranulin-RAGE interaction leading toinflammatory diseases, 1′-amyloid-RAGE interaction leading toAlzheimer's Disease, and amphoterin-RAGE interaction leading to cancer.

I. RAGE and the Complications of Diabetes

As noted above, the compounds of the present invention are useful in thetreatment of the complications of diabetes. It has been shown thatnonenzymatic glycoxidation of macromolecules ultimately resulting in theformation of advanced glycation endproducts (AGEs) is enhanced at sitesof inflammation, in renal failure, in the presence of hyperglycemia andother conditions associated with systemic or local oxidant stress (Dyer,D., et al., J. Clin. Invest., 91:2463-2469 (1993); Reddy, S., et al.,Biochem., 34:10872-10878 (1995); Dyer, D., et al., J. Biol. Chem.,266:11654-11660 (1991); Degenhardt, T., et al., Cell Mol. Biol.,44:1139-1145 (1998)). Accumulation of AGEs in the vasculature can occurfocally, as in the joint amyloid composed of AGE-β₂-microglobulin foundin patients with dialysis-related amyloidosis (Miyata, T., et al., J.Clin. Invest., 92:1243-1252 (1993); Miyata, T., et al., J. Clin.Invest., 98:1088-1094 (1996)), or generally, as exemplified by thevasculature and tissues of patients with diabetes (Schmidt, A-M., etal., Nature Med., 1:1002-1004 (1995)). The progressive accumulation ofAGEs over time in patients with diabetes suggests that endogenousclearance mechanisms are not able to function effectively at sites ofAGE deposition. Such accumulated AGEs have the capacity to altercellular properties by a number of mechanisms. Although RAGE isexpressed at low levels in normal tissues and vasculature, in anenvironment where the receptor's ligands accumulate, it has been shownthat RAGE becomes upregulated (Li, J. et at, J. Biol. Chem.,272:16498-16506 (1997); Li, J., et al., J. Biol. Chem., 273:30870-30878(1998); Tanaka, N., et al., J. Biol. Chem., 275:25781-25790 (2000)).RAGE expression is increased in endothelium, smooth muscle cells andinfiltrating mononuclear phagocytes in diabetic vasculature. Also,studies in cell culture have demonstrated that AGE-RAGE interactioncaused changes in cellular properties important in vascular homeostasis.

II. RAGE and Cellular Dysfunction in the Amyloidoses

Also as noted above, the compounds of the present invention are usefulin treating amyloidoses and Alzheimer's disease. RAGE appears to be acell surface receptor which binds s-sheet fibrillar material regardlessof the composition of the subunits (amyloid-β peptide, Aβ, amylin, serumamyloid A, prion-derived peptide) (Yan, S.-D., et al., Nature,382:685-691 (1996); Yan, S-D., et al., Nat. Med., 6:643-651 (2000)).Deposition of amyloid has been shown to result in enhanced expression ofRAGE. For example, in the brains of patients with Alzheimer's disease(AD), RAGE expression increases in neurons and glia (Yan, S.-D., et al.,Nature 382:685-691 (1996)). The consequences of interaction with RAGEappear to be quite different on neurons versus microglia. Whereasmicroglia become activated as a consequence of Aβ-RAGE interaction, asreflected by increased motility and expression of cytokines, earlyRAGE-mediated neuronal activation is superceded by cytotoxicity at latertimes. Further evidence of a role for RAGE in cellular interactions ofAβ concerns inhibition of AB-induced cerebral vasoconstriction andtransfer of the peptide across the blood-brain barrier to brainparenchyma when the receptor was blocked (Kumar, S., et al., Neurosci.Program, p 141-#275.19 (2000)). Inhibition of RAGE-amyloid interactionhas been shown to decrease expression of cellular RAGE and cell stressmarkers (as well as NF-kB activation), and diminish amyloid deposition(Yan, S-D., et al., Nat. Med., 6:643-651 (2000)) suggesting a role forRAGE-amyloid interaction in both perturbation of cellular properties inan environment enriched for amyloid (even at early stages) as well as inamyloid accumulation.

III. RAGE and Propagation of the Immune/Inflammatory Response

As noted above, the compounds of the present invention are useful intreating inflammation. For example, S100/calgranulins have been shown tocomprise a family of closely related calcium-binding polypeptidescharacterized by two EF-hand regions linked by a connecting peptide(Schafer, B. et al., TIBS, 21:134-140 (1996); Zimmer, D., et al., BrainRes. Bull., 37:417-429 (1995); Rammes, A., et al., J. Biol. Chem.,272:9496-9502 (1997); Lugering, N., et al., Eur. J. Clin. Invest.,25:659-664 (1995)). Although they lack signal peptides, it has long beenknown that S100/calgranulins gain access to the extracellular space,especially at sites of chronic immune/inflammatory responses, as incystic fibrosis and rheumatoid arthritis. RAGE is a receptor for manymembers of the S100/calgranulin family, mediating their proinflammatoryeffects on cells such as lymphocytes and mononuclear phagocytes. Also,studies on delayed-type hypersensitivity response, colitis in IL-10 nullmice, collagen-induced arthritis, and experimental autoimmuneencephalitis models suggest that RAGE-ligand interaction (presumablywith S100/calgranulins) has a proximal role in the inflammatory cascadeas implicated in the inflammatory diseases such as but not limited torheumatoid arthritis and multiple sclerosis.

RAGE is also implicated in inflammatory diseases of the skin such as butnot limited to atopic dermatitis, eczema, and psoriasis. Psoriasis inparticular is characterized by inflamed itchy lesions. Psoriasis may beaccompanied by arthropathic symptoms that are similar to those in seenin rheumatoid arthritis.

There is considerable evidence that psoriasis is a polygenic autoimmunedisorder. Psoriatic lesions are rich in cytokines, in particular IL-1and IL-8, both potent proinflammatory mediators. IL-8 in particular is achemotactic factor for neutrophils; neutrophils are also known tosynthesize and secrete S100 proteins, one of the ligands for RAGE whichis implicated in propogation of the immune and inflammatory response.Psoriasin (S100A7) a new member of the S100 gene family, is a secretedprotein isolated from psoriatic skin. Semprini et. al. (Hum. Genet. 2002October, 111(4-5), 310-3) have shown a linkage of psoriasis geneticsusceptibility to distinct overexpression of S100 proteins in skin.Therefore, a modulator of RAGE would be expected to regulate the immuneresponse in psoriasis.

IV. RAGE and Amphoterin

As noted above, the compounds of the present invention are useful intreating tumor and tumor metastasis. For example, amphoterin is a highmobility group I nonhistone chromosomal DNA binding protein (Rauvala,H., et al., J. Biol. Chem., 262:16625-16635 (1987); Parkikinen, J., etal., J. Biol. Chem. 268:19726-19738 (1993)) which has been shown tointeract with RAGE. It has been shown that amphoterin promotes neuriteoutgrowth, as well as serving as a surface for assembly of proteasecomplexes in the fibrinolytic system (also known to contribute to cellmobility). In addition, a local tumor growth inhibitory effect ofblocking RAGE has been observed in a primary tumor model (C6 glioma),the Lewis lung metastasis model (Taguchi, A., et al., Nature 405:354-360(2000)), and spontaneously arising papillomas in mice expressing thev-Ha-ras transgene (Leder, A., et al., Proc. Natl. Acad. Sci.,87:9178-9182 (1990)).

Amphoterin is a high mobility group I nonhistone chromosomal DNA bindingprotein (Rauvala, H. and R. Pihlaskari. 1987. Isolation and somecharacteristics of an adhesive factor of brain that enhances neuriteoutgrowth in central neurons. J. Biol. Chem. 262:16625-16635.(Parkikinen, J., E. Raulo, J. Merenmies, R. Nolo, E. Kajander, M.Baumann, and H. Rauvala. 1993. Amphoterin, the 30 kDa protein in afamily of HIMG1-type polypeptides. J. Biol. Chem. 268:19 726-19738).

V. RAGE and Erectile Dysfunction

Relaxation of the smooth muscle cells in the cavernosal arterioles andsinuses results in increased blood flow into the penis, raising corpuscavernosum pressure to culminate in penile erection. Nitric oxide isconsidered the principle stimulator of cavernosal smooth musclerelaxation (See Wingard C J, Clinton W, Branam H, Stopper V S, Lewis RW, Mills T M, Chitaley K. Antagonism of Rho-kinase stimulates rat penileerection via a nitric oxide-independent pathway. Nature Medicine 2001January; 7(1):119-122). RAGE activation produces oxidants (See Yan,S-D., Schmidt A-M., Anderson, G., Zhang, J., Brett, J., Zou, Y-S.,Pinsky, D., and Stern, D. Enhanced cellular oxidant stress by theinteraction of advanced glycation endproducts with theirreceptors/binding proteins. J. Biol. Chem. 269:9889-9887, 1994.) via anNADH oxidase-like enzyme, therefore suppressing the circulation ofnitric oxide. Potentially by inhibiting the activation of RAGE signalingpathways by decreasing the intracellular production of AGEs, generationof oxidants will be attenuated. RAGE blockers may promote and facilitatepenile erection by blocking the access of ligands to RAGE.

The calcium-sensitizing Rho-kinase pathway may play a synergistic rolein cavernosal vasoconstriction to maintain penile flaccidity. Theantagonism of Rho-kinase results in increased corpus cavernosumpressure, initiating the erectile response independently of nitric oxide(Wingard et al.). One of the signaling mechanisms activated by RAGEinvolves the Rho-kinase family such as cdc42 and rac (See Huttunen H J,Fages C, Rauvala H. Receptor for advanced glycation end products(RAGE)-mediated neurite outgrowth and activation of NF-kappaB requirethe cytoplasmic domain of the receptor but different downstreamsignaling pathways. J Biol Chem 1999 Jul. 9; 274(28):19919-24). Thus,inhibiting activation of Rho-kinases via suppression of RAGE signalingpathways will enhance and stimulate penile erection independently ofnitric oxide.

VI. RAGE and Respiratory Diseases

Airway inflammation is important in the pathogenesis of asthma. Suchinflammation may give rise to significant exacerbations and increases inasthma severity, as well as to be a major factor in a decline inasthmatic status. In severe exacerbations of asthma there is an intense,mechanistically heterogeneous inflammatory response involving neutrophiland eosinophil accumulation and activation. Neutrophils are asignificant source of S100 proteins, key ligands for RAGE implicated inthe propogation of the immune response and inflammation. Therefore,modulators of RAGE would be expected to possess therapeutic value in thetreatment of asthma.

Further, the propogation step in the immune response in the lung drivenby S100-RAGE interaction would be expected to lead to the activationand/or recruitment of inflammatory cells, such as neutrophils, which inchronic obstructive pulmonary diseases such as emphysema, aresignificant sources of damaging proteases. Therefore, a RAGE modulatorwould be expected possess potential in the treatment of chronicobstructive pulmonary diseases.

Thus, in a further aspect, the present invention provides a method forthe inhibition of the interaction of RAGE with physiological ligands. Ina preferred embodiment of this aspect, the present invention provides amethod for treating a disease state selected from the group consistingof acute and chronic inflammation including but not limited to skininflammation such as psoriasis and atopic dermatitis and lunginflammation including asthma and chronic obstructive pulmonary disease,vascular permeability, nephropathy, atherosclerosis, retinopathy,Alzheimer's disease, erectile dysfunction, and tumor invasion and/ormetastasis, which comprises administering to a subject in need thereof acompound of the present invention, preferably a pharmacologicallyeffective amount, more preferably a therapeutically effective amount. Ina preferred embodiment, at least one compound of Formula (I) isutilized, either alone or in combination with one or more knowntherapeutic agents. In a further preferred embodiment, the presentinvention provides method of prevention and/or treatment of RAGEmediated human diseases, treatment comprising alleviation of one or moresymptoms resulting from that disorder, to an outright cure for thatparticular disorder or prevention of the onset of the disorder, themethod comprising administration to a human in need thereof atherapeutically effective amount of a compound of the present invention,preferably a compound of Formula (I).

In this method, factors which will influence what constitutes aneffective amount will depend upon the size and weight of the subject,the biodegradability of the therapeutic agent, the activity of thetherapeutic agent, as well as its bioavailability. As used herein, thephrase “a subject in need thereof” includes mammalian subjects,preferably humans, who either suffer from one or more of the aforesaiddiseases or disease states or are at risk for such. Accordingly, in thecontext of the therapeutic method of the invention, this method also iscomprised of a method for treating a mammalian subject prophylactically,or prior to the onset of diagnosis such disease(s) or disease state(s).

In a further aspect of the present invention, the RAGE modulators of theinvention are utilized in adjuvant therapeutic or combinationtherapeutic treatments with other known therapeutic agents.

The term “treatment” as used herein, refers to the full spectrum oftreatments for a given disorder from which the patient is suffering,including alleviation of one, most of all symptoms resulting from thatdisorder, to an outright cure for the particular disorder or preventionof the onset of the disorder.

The following is a non-exhaustive listing of adjuvants and additionaltherapeutic agents which may be utilized in combination with the RAGEmodulators of the present invention:

Pharmacologic classifications of anticancer agents:

-   1. Alkylating agents: Cyclophosphamide, nitrosoureas, carboplatin,    cisplatin, procarbazine-   2. Antibiotics: Bleomycin, Daunorubicin, Doxorubicin-   3. Antimetabolites: Methotrexate, Cytarabine, Fluorouracil-   4. Plant alkaloids: Vinblastine, Vincristine, Etoposide, Paclitaxel,-   5. Hormones: Tamoxifen, Octreotide acetate, Finasteride, Flutamide-   6. Biologic response modifiers: Interferons, Interleukins,    Anti-tumor antibodies

Pharmacologic classifications of treatment for Rheumatoid Arthritis(Inflammation)

-   1. Analgesics: Aspirin-   2. NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen,    Naproxen, Diclofenac-   3. DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate,    gold preparations, hydroxychloroquine, sulfasalazine-   4. Biologic Response Modifiers, DMARDs: Etanercept, Infliximab    Glucocorticoids

Pharmacologic classifications of treatment for Diabetes Mellitus

-   1. Sulfonylureas: Tolbutamide, Tolazamide, Glyburide, Glipizide-   2. Biguanides: Metformin-   3. Miscellaneous oral agents: Acarbose, Troglitazone-   4. Insulin

Pharmacologic classifications of treatment for Alzheimer's Disease

-   1. Cholinesterase Inhibitor: Tacrine, Donepezil-   2. Antipsychotics: Haloperidol, Thioridazine-   3. Antidepressants: Desipramine, Fluoxetine, Trazodone, Paroxetine-   4. Anticonvulsants: Carbamazepine, Valproic acid

In a further preferred embodiment, the present invention provides amethod of treating RAGE mediated diseases, the method comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of Formula (I) in combination with therapeuticagents selected from the group consisting of alkylating agents,antimetabolites, plant alkaloids, antibiotics, hormones, biologicresponse modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids,sulfonylureas, biguanides, insulin, cholinesterase inhibitors,antipsychotics, antidepressants, and anticonvulsants. In a furtherpreferred embodiment, the present invention provides the pharmaceuticalcomposition of the invention as described above, further comprising oneor more therapeutic agents selected from the group consisting ofalkylating agents, antimetabolites, plant alkaloids, antibiotics,hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs,glucocorticoids, sulfonylureas, biguanides, insulin, cholinesteraseinhibitors, antipsychotics, antidepressants, and anticonvulsants.

Generally speaking, the compound of the present invention, preferablyFormula (I), is administered at a dosage level of from about 0.01 to 500mg/kg of the body weight of the subject being treated systemically, witha preferred dosage range between 0.01 and 200 mg/kg, most preferably 0.1to 100 mg/kg of body weight per day. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage will vary depending upon the host treated and the particular modeof administration. For example, a formulation intended for oraladministration to humans may contain 1 mg to 2 grams of a compound ofFormula (I) with an appropriate and convenient amount of carriermaterial which may vary from about 5 to 95 percent of the totalcomposition. Also a dosage form intended for topical administration tothe skin may be prepared at 0.1% to 99% compound to topical excipientratio and a dosage form intended for inhaled administration of 0.01 to200 mg of compound in a suitable carrier to deliver an inhaled dosage ofcompound. Dosage unit forms of systemically delivered compound willgenerally contain between from about 5 mg to about 500 mg of activeingredient. This dosage has to be individualized by the clinician basedon the specific clinical condition of the subject being treated. Thus,it will be understood that the specific dosage level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forRAGE-mediated disease(s). Likewise, the specific pharmacologicalresponses observed may vary according to and depending on the particularactive compound selected or whether there are present pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention.

1.-7. (canceled)
 8. A method for treating retinopathy in a subject having retinopathy comprising administering to the subject a therapeutically effective amount of a compound of Formula (Ib):

wherein R₁ is -hydrogen, -alkyl, or -alkenyl, R₃ is -hydrogen or -alkyl, and R₁₀₂ and R₁₀₄ are independently selected from the group consisting of: a) —H, b) -alkyl, c) -aryl, d) -heteroaryl, e) -alkylene-heteroaryl-aryl, f) -alkylene-aryl, g) -alkylene-W₂—R₁₈, h) —Y₄—NR₂₃R₂₄, i) —Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, j) —Y₄—C(═NR₂₅)NR₂₃R₂₄, and k) —Y₄—Y₅-A₂; wherein W₂ is —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

wherein R₁₉ and R₂₀ are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; R₁₈ is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl; Y₅ is a direct bond, —CH₂—, —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

wherein R₂₇ and R₂₆ are independently selected from the group consisting of -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkyl-O-aryl; Y₄ is a) -alkylene, b) -alkenylene, c) -alkynylene, d) -arylene, e) -heteroarylene, f) -cycloalkylene, g) -heterocyclylene, h) -alkylene-arylene, i) -alkylene-heteroarylene, j) -alkylene-cycloalkylene, k) -alkylene-heterocyclylene, l) -arylene-alkylene, m) -heteroarylene-alkylene, n) -cycloalkylene-alkylene, o) -heterocyclylene-alkylene, p) —O—, q) —S—, r) —S(O₂)—, or s) —S(O)—; wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO₂ atoms; A₂ is a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or b) -imidazolyl, R₂₃, R₂₄, and R₂₅ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R₂₃ and R₂₄ may be taken together to form a five-membered ring having the formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen atom to which R₂₃ and R₂₄ are attached wherein s and t are, independently, 1, 2, 3, or 4; X₃ is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

wherein R₂₈ and R₂₉ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl; wherein the alkyl and/or aryl groups of R₁₀₂ and R₁₀₄ may be optionally substituted 1-4 times with a substituent group selected from the group consisting of: a) halogen, b) perhaloalkyl, c) alkyl, d) cyano, e) alkyloxy, f) aryl, and g) aryloxy wherein the ring or rings containing a heteroatom in the heteroaryl, heterarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl, or fused heteroarylheterocyclyl groups in R₁₀₂ or R₁₀₄ or in a substituent of R₁₀₂ or R₁₀₄ is a five-membered nitrogen containing ring, or a pharmaceutically acceptable salt thereof, and wherein a therapeutically effective amount comprises sufficient compound to at least partially inhibit the binding of a ligand to RAGE.
 9. The method according to claim 8, wherein the compound is mixed with a pharmaceutically acceptable carrier.
 10. The method according to claim 8, wherein the compound is administered parenterally, orally, topically, rectally or by inhalation as a spray.
 11. The method according to claim 8, wherein the compound comprises a dosage ranging from 0.01 to 500 mg/kg/day.
 12. The method according to claim 8, wherein the compound comprises a dosage ranging from 0.01 to 200 mg/kg/day.
 13. The method according to claim 8, wherein the compound comprises a dosage ranging from 0.1 to 100 mg/kg/day.
 14. The method according to claim 8, wherein the compound comprises a dosage ranging from 5 to 500 mg/kg/day.
 15. A method for treating retinopathy in a subject having retinopathy comprising administering to the subject a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and wherein a therapeutically effective amount comprises sufficient [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof to at least partially inhibit the binding of a ligand to RAGE.
 16. The method according to claim 15, wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier.
 17. The method according to claim 15, wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof is administered parenterally, orally, topically, rectally or by inhalation as a spray.
 18. The method according to claim 15, wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 0.01 to 500 mg/kg/day.
 19. The method according to claim 15, wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 0.01 to 200 mg/kg/day.
 20. The method according to claim 15, wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 0.01 to 100 mg/kg/day.
 21. The method according to claim 15, wherein the [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof comprises a dosage ranging from 5 to 500 mg/kg/day.
 22. The method according to claim 8, wherein the retinopathy is diabetic retinopathy.
 23. The method according to claim 15, wherein the retinopathy is diabetic retinopathy. 